Pulmonary delivery in treating disorders of the central nervous system

ABSTRACT

A method for treating a disorder of the central nervous system includes administering to the respiratory tract of a patient a drug which is delivered to the pulmonary system, for instance to the alveoli or the deep lung. The drug is administered at a dose which is at least about two-fold less than the dose required by oral administration. Particles that include the drug can be employed. Preferred particles have a tap density of less than about 0.4 g/cm 3 . In addition to the medicament, the particles can include other materials such as, for example, phospholipids, amino acids, combinations thereof and others.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.10/762,200, filed Jan. 21, 2004, which is a continuation of U.S.application Ser. No. 10/441,968, filed May 20, 2003, which is acontinuation of U.S. application Ser. No. 09/877,734, filed Jun. 8,2001, which is a continuation-in-part of U.S. application Ser. No.09/665,252, filed on Sep. 19, 2000. The entire teachings of the aboveapplications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] Parkinson's disease is characterized neuropathologically bydegeneration of dopamine neurons in the basal ganglia and neurologicallyby debilitating tremors, slowness of movement and balance problems. Itis estimated that over one million people suffer from Parkinson'sdisease. Nearly all patients receive the dopamine precursor levodopa orL-Dopa, often in conjunction with the dopa-decarboxylase inhibitor,carbidopa. L-Dopa adequately controls symptoms of Parkinson's disease inthe early stages of the disease. However, it tends to become lesseffective after a period which can vary from several months to severalyears in the course of the disease.

[0003] It is believed that the varying effects of L-Dopa in Parkinson'sdisease patients is related, at least in part, to the plasma half lifeof L-Dopa which tends to be very short, in the range of 1 to 3 hours,even when co-administered with carbidopa. In the early stages of thedisease, this factor is mitigated by the dopamine storage capacity ofthe targeted striatal neurons. L-Dopa is taken up and stored by theneurons and is released over time. However, as the disease progresses,dopaminergic neurons degenerate, resulting in decreased dopamine storagecapacity. Accordingly, the positive effects of L-Dopa becomeincreasingly related to fluctuations of plasma levels of L-Dopa. Inaddition, patients tend to develop problems involving gastric emptyingand poor intestinal uptake of L-Dopa. Patients exhibit increasinglymarked swings in Parkinson's disease symptoms, ranging from a return toclassic Parkinson's disease symptoms, when plasma levels fall, to theso-called dyskinesis, when plasma levels temporarily rise too highfollowing L-Dopa administration.

[0004] As the disease progresses, conventional L-Dopa therapy involvesincreasingly frequent, but lower dosing schedules. Many patients, forexample, receive L-Dopa every two to three hours. It is found, however,that even frequent doses of L-Dopa are inadequate in controllingParkinson's disease symptoms. In addition, they inconvenience thepatient and often result in non-compliance.

[0005] It is also found that even with as many as six to ten L-Dopadoses a day, plasma L-Dopa levels can still fall dangerously low, andthe patient can experience very severe Parkinson's disease symptoms.When this happens, additional L-Dopa is administered as interventiontherapy to rapidly increase brain dopamine activity. However, orallyadministered therapy is associated with an onset period of about 30 to45 minutes during which the patient suffers unnecessarily. In addition,the combined effects of the intervention therapy, with the regularlyscheduled dose can lead to overdosing, which can requirehospitalization. For example, subcutaneously administered dopaminereceptor agonist (apomorphine), often requiring a peripherally actingdopamine antagonist, for example, domperidone, to controldopamine-induced nausea, is inconvenient and invasive.

[0006] Other medical indications involving the central nervous system(CNS) require rapid delivery of a medicament such as but not limited toepilepsy, panic attacks and migraines. For example, about 2 millionpeople in the USA suffer from some form of epilepsy, with the majorityreceiving at least one of several different anti-seizure medications.The incidence of status epilepticus (the more serious form of epilepsy)is approximately 250,000. A significant number of patients also sufferfrom so-called “cluster seizures”, wherein an initial seizure forewarnsthat a series of additional seizures will occur within a relativelyshort time frame. By some reports, 75% of all patients continue toexperience seizures despite taking medication chronically. Poorcompliance with the prescribed medications is believed to be asignificant (albeit not sole) contributing factor. The importance ofcontrolling or minimizing the frequency and intensity of seizures liesin the fact that incidence of seizures has been correlated with neuronaldeficits and is believed to cause loss of neurons in the brain.

[0007] Despite chronic treatment, as many as 75% of all patientscontinue to exhibit periodic seizures. The uncontrolled seizures occurin many forms. In the case of “cluster seizures,” one seizure servesnotice that a cascade has begun which will lead to a series of seizuresbefore the total episode passes. In certain patients, prior to the onsetof a severe seizure, some subjective feeling or sign is detected by thepatient (defined as an aura). In both instances, an opportunity existsfor these patients to significantly reduce the liability of the seizurethrough “self medication”. While many patients are instructed to do so,the drugs currently available to permit effective self medication arelimited.

[0008] Panic attacks purportedly affect at least about 2,5 millionpeople in this country alone. The disorder is characterized by acuteepisodes of anxiety, leading to difficult breathing, dizziness, heartpalpitations and fear of losing control. The disorder is believed toinvolve a problem with the sympathetic nervous system (involving anexaggerated arousal response, leading to overstimulation of adrenalinerelease and/or adrenergic neurons). Current pharmacotherapy combinesselective serotonin re-uptake inhibitors (SSRIs), or otherantidepressant medications, with the concomitant use of benzodiazapines.

[0009] A limitation of the pharmacotherapies in current use is the delayin the onset of efficacy at the beginning of treatment. Like treatmentsfor depression, the onset of action of the SSRIs requires weeks ratherthan days. The resulting requirement for continuous prophylactictreatment can, in turn, lead to significant compliance problemsrendering the treatment less effective. Therefore, there is a need forrapid onset therapy at the beginning of treatment to manage theanticipation of the panic attacks, as well as a treatment for abortingany attacks as soon as possible after their occurrence.

[0010] A pure vasogenic etiology/pathogenesis for migraine was firstproposed in the 1930s; by the 1980s, this was replaced by a neurogenicetiology/pathogenesis, which temporarily won favor among migraineinvestigators. However, it is now generally recognized that bothvasogenic and neurogenic components are involved, interacting as apositive feedback system, with each continuously triggering the other.The major neurotransmitters implicated include serotonin (the site ofaction of the triptans), substance P (traditionally associated withmediating pain), histamine (traditionally associated with inflammation)and dopamine. The major pathology associated with migraine attacksinclude an inflammation of the dura, an increase in diameter ofmeningeal vessels and supersensitivity of the trigeminal cranial nerve,including the branches that enervate the meningeal vessels. The triptansare believed to be effective because they affect both the neural andvascular components of the migraine pathogenic cascade. Migrainesinclude Classic and Common Migraines, Cluster Headaches and TensionHeadaches.

[0011] Initial studies with sumatriptain showed that, when administeredintravenously (IV), a 90% efficacy rate was achieved. However, theefficiency rate is only approximately 60% with the oral form (versus 30%for placebo). The nasal form has proven to be highly variable, requiringtraining and skill on the part of the patient, which some of thepatients do not seem to master. The treatment also induces a bad tastein the mouth which many patients find highly objectionable. Therecurrently exists no clear evidence that any of the recent, moreselective 5HT1 receptor agonists are any more efficacious thansumatriptan (which stimulates multiple receptor subtypes; e.g., 1B, 1D,and 1F).

[0012] In addition to not providing adequate efficacy, current dosing oftriptans have at least two other deficiencies: (1) vasoconstriction ofchest and heart muscles, which produces chest tightness and pain in somesubjects; this effect also presents an unacceptable risk to hypertensiveand other CV patients, for whom the triptans are contraindicated, and(2) the duration of action of current formulations is limited, causing areturn of headache in many patients about 4 hours after initialtreatment.

[0013] Rapid onset of a hypnotic would also be quite desirable andparticularly useful in sleep restoration therapy, as middle of nightawakening and difficulty in falling asleep again, once awakened, iscommon in middle aged and aging adults.

[0014] Other indications related to the CNS, such as, for example,mania, bipolar disorders, schizophrenia, appetite suppression, motionsickness, nausea and others, as known in the art, also require rapiddelivery of a medicament to its site of action.

[0015] Therefore, a need exists for methods of delivery of medicamentswhich are at least as effective as conventional therapies yet minimizeor eliminate the above-mentioned problems.

SUMMARY OF THE INVENTION

[0016] The invention relates to methods of treating disorders of thecentral nervous system (CNS). More specifically the invention relates tomethods of delivering a drug suitable in treating a disorder of the CNSto the pulmonary system and include administering to the respiratorytract of a patient in need of treatment particles comprising aneffective amount of the medicament. In one embodiment, the patient is inneed of rapid onset of the treatment, for instance in need of rescuetherapy; the medicament is released into the patient's blood stream andreaches the medicament's site of action in a time interval which issufficiently short to provide the rescue therapy or rapid treatmentonset. In another embodiment, the invention is related to providingongoing, non-rescue therapy to a patient suffering with a disorder ofthe CNS.

[0017] Disorders of the nervous system include, for example, Parkinson'sdisease, epileptic and other seizures, panic attacks, sleep disorders,migraines, attention deficit hyperactivity disorders, Alzheimer'sdisease, bipolar disorders, obsessive compulsive disorders and others.

[0018] The methods of the invention are particularly useful in theongoing treatment and for rescue therapy in the course of Parkinson'sdisease. The drug or medicament employed in the methods of the inventionis a dopamine precursor or a dopamine agonist, for example, levodopa(L-DOPA).

[0019] In one embodiment, the invention is related to a method fortreating Parkinson's disease includes administering to the respiratorytract of a patient in need of treatment or rescue therapy a drug fortreating Parkinson's disease, e.g., L-Dopa. The drug is delivered to thepulmonary system, for instance to the alveoli region of the lung. Incomparison to oral administration, at least about a two fold dosereduction is employed. Doses generally are between about two times andabout ten times less than the dose required with oral administration.

[0020] In other embodiments, a method for treating a disorder of the CNSincludes administering to the respiratory tract of a patient in need oftreatment a drug for treating the disorder. The drug is administered ina dose which is at least about two times less than the dose requiredwith oral administration and is delivered to the pulmonary system.

[0021] The doses employed in the invention generally also are at leastabout two times less than the dose required with routes ofadministration other than intravenous, such as, for instance,subcutaneous injection, intramuscular injection, intra-peritoneal,buccal, rectal and nasal.

[0022] The invention further is related to methods for administering tothe pulmonary system a therapeutic dose of the medicament in a smallnumber of steps, and preferably in a single, breath activated step. Theinvention also is related to methods of delivering a therapeutic dose ofa drug to the pulmonary system, in a small number of breaths, andpreferably in a single breath. The methods include administeringparticles from a receptacle which has a mass of particles, to asubject's respiratory tract. Preferably, the receptacle has a volume ofat least about 0.37 cm³ and can have a design suitable for use in a drypowder inhaler. Larger receptacles having a volume of at least about0.48 cm³, 0.67 cm³ or 0.95 cm³ also can be employed. The receptacle canbe held in a single dose breath activated dry powder inhaler.

[0023] In one embodiment of the invention, the particles deliver atleast about 10 milligrams (mg) of the drug. In other embodiments, theparticles deliver at least about 15, 20, 25, 30 milligrams of drug.Higher amounts can also be delivered, for example the particles candeliver at least about 35, 40 or 50 milligrams of drug.

[0024] The invention also is related to methods for the efficientdelivery of particles to the pulmonary system. In one embodiment, theinvention is related to delivering to the pulmonary system particlesthat represent at least about 70% and preferably at least about 80% ofthe nominal powder dose. In another embodiment of the invention, amethod of delivering a medicament to the pulmonary system, in a single,breath-activated step, includes administering particles, from areceptacle which has a mass of particles, to the respiratory tract of asubject, wherein at least 50% of the mass of particles is delivered.

[0025] Preferably, administration to the respiratory tract is by a drypowder inhaler or by a metered dose inhaler. The particles of theinvention also can be employed in compositions suitable for delivery tothe pulmonary system such as known in the art.

[0026] In one embodiment, particles employed in the method of theinvention are particles suitable for delivering a medicament to thepulmonary system and in particular to the alveoli or the deep lung. In apreferred embodiment, the particles -have a tap density which is lessthan 0.4 g/cm³. In another preferred embodiment, the particles have ageometric diameter, of at least 5 μm (microns), preferably between about5 μm and 30 μm. In yet another preferred embodiment, the particles havean aerodynamic diameter between about 1 μm and about 5 μm. In anotherembodiment, the particles have a mass median geometric diameter (MMGD)larger than 5 μm, preferably around about 10 μm or larger. In yetanother embodiment, the particles have a mass median aerodynamicdiameter (MMAD) ranging from about 1 μm to about 5 μm. In a preferredembodiment, the particles have an MMAD ranging from about 1 μm to bout 3μm.

[0027] Particles can consist of the medicament or can further includeone or more additional components. Rapid release of the medicament intothe blood stream and its delivery to its site of action, for example,the central nervous system, is preferred. In one embodiment of theinvention, the particles include a material which enhances the releasekinetics of the medicament. Examples of suitable such materials include,but are not limited to, certain phospholipids, amino acids, carboxylatemoieties combined with salts of multivalent metals and others.

[0028] In a preferred embodiment, the energy holding the particles ofthe dry powder in an aggregated state is such that a patient's breath,over a reasonable physiological range of inhalation flow rates issufficient to deaggregate the powder contained in the receptacle intorespirable particles. The deaggregated particles can penetrate via thepatient's breath into and deposit in the airways and/or deep lung withhigh efficiency.

[0029] The invention has many advantages. For example, pulmonarydelivery provides on-demand treatment without the inconvenience ofinjections. Selective delivery of a medicament to the central nervoussystem can be obtained in a time frame not available with otheradministration routes, in particular conventional oral regimens. Thus,an effective dose can be delivered to the site of action on the “firstpass” of the medicament in the circulatory system. By practicing theinvention, relief is available to symptomatic patients in a time frameduring which conventional oral therapies would still be traveling to thesite of action. The reduced doses employed in the methods of theinvention result in a plasma drug level which is equivalent to thatobtained with the oral dose. Blood plasma levels approaching thoseobserved with intravenous administration can be obtained. Doseadvantages over other routes of administration, e.g., intramuscular,subcutaneous, intra-peritoneal, buccal, rectal and nasal, also can beobtained. Furthermore, a therapeutic amount of the drug can be deliveredto the pulmonary system in one or a small number of steps or breaths.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030]FIG. 1A is a plot representation of blood levels of L-Dopa in ratsfollowing administration via oral gavage or direct administration to thelungs measured by mass spectrometer.

[0031]FIG. 1B is a plot representation of blood levels of L-Dopa in ratsfollowing administration via oral gavage or direct administration to thelungs measured by HPLC.

[0032]FIG. 2A is a plot representation of blood L-Dopa levels in ratsfollowing delivery orally or directly into the lungs.

[0033]FIG. 2B is a plot representation of striatal dopamine levels inrats following delivery of L-Dopa orally or directly into the lungs.

[0034]FIG. 3 is a plot representation of blood and striatal levels of¹⁴C following administration of ¹⁴C-L-Dopa either orally or directly tothe lungs.

[0035]FIG. 4 is a plot representation of plasma ¹⁴C levels in ratsfollowing ¹⁴C-L-Dopa administration via oral (gavage), tracheotomy orventilator.

[0036]FIG. 5 is a plot representation of brain ¹⁴C levels in ratsfollowing ¹⁴C-L-Dopa administration via oral (gavage), tracheotomy orventilator.

[0037]FIG. 6A is a bar graph showing absolute ¹⁴C-Carboplatin levels inregions of the brain following intravenous (IV) and pulmonary (lung)administration.

[0038]FIG. 6B is a bar graph showing relative ¹⁴C-Carboplatin levels inregions of the brain following intravenous (IV) and pulmonary (lung)administration.

[0039]FIG. 7A is a bar graph showing absolute ¹⁴C-Carboplatin levels inanimal organs following intravenous (IV) or pulmonary (lung)administration.

[0040]FIG. 7B shows relative ¹⁴C-Carboplatin levels in animal organsfollowing intravenous (IV) or pulmonary (lung) administration.

[0041]FIG. 8 is a plot representation showing plasma concentration ofL-Dopa vs. time following oral or pulmonary administration (normalizedfor an 8 mg dose).

[0042]FIG. 9 is a plot representation showing plasma concentration ofketoprofen vs. time for oral and pulmonary groups.

[0043]FIG. 10 is a plot representation showing plasma concentration ofketoprofen vs. time for oral group

[0044]FIG. 11 is a plasma concentration of ketoprofen vs. time forpulmonary group.

[0045]FIG. 12 is a plot showing RODOS curves for different powderformulations that include L-DOPA.

[0046]FIGS. 13A and 13B are HPLC chromatograms that depict L-DOPArecovery from powders (FIG. 13A) compared to a blank sample (FIG. 13B).

[0047]FIG. 14A depicts L-DOPA plasma levels following pulmonary (lung),and oral routes.

[0048]FIG. 14B depicts L-DOPA plasma levels following pulmonary (lung),oral and intravenous administration.

[0049]FIGS. 15A and 15B show results, respectively, of oral (p.o.) andpulmonary (lung) L-DOPA on functional “placing task” in a rat model ofParkinson's disease.

[0050]FIGS. 16A and 16B show results, respectively of oral (p.o.) andpulmonary (lung) L-DOPA on functional “bracing task” in a rat model ofParkinson's disease.

[0051]FIGS. 17A and 17B show results, respectively of oral (p.o.) andpulmonary (lung) L-DOPA on functional akinesia task in a rat model ofParkinson's disease.

[0052]FIG. 18 shows results of oral (p.o.) and pulmonary (lung) deliveryof L-DOPA on functional rotation in a rat model of Parkinson's disease.

[0053]FIG. 19A depicts time to seizure onset after delivery of pulmonaryand oral alprazolam 10 minutes prior to PZT administration.

[0054]FIG. 19B depicts duration of seizure after delivery of pulmonaryand oral alprazolam 10 minutes prior to PZT administration.

[0055]FIG. 20A depicts time to seizure onset after delivery of pulmonaryand oral alprazolam 30 minutes prior to PZT administration.

[0056]FIG. 20B depicts duration of seizure after delivery of pulmonaryand oral alprazolam 30 minutes prior to PZT administration.

[0057]FIG. 21 A depicts time to seizure onset for pulmonary alprazolam10 and 30 minutes prior to PZT administration.

[0058]FIG. 21B depicts duration of seizure for pulmonary alprazolam 10and 30 minutes prior to PZT administration.

DETAILED DESCRIPTION OF THE INVENTION

[0059] The features and other details of the invention, either as stepsof the invention or as combination of parts of the invention, will nowbe more particularly described and pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprinciple feature of this invention may be employed in variousembodiments without departing from the scope of the invention.

[0060] The invention is generally related to methods of treatingdisorders of the CNS. In particular, the invention is related to methodsfor pulmonary delivery of a drug, medicament or bioactive agent.

[0061] One preferred medical indication which can be treated by themethod of the invention is Parkinson's disease, in particular during thelate stages of the disease, when the methods described hereinparticularly well suited to provide rescue therapy. As used herein,“rescue therapy” means on demand, rapid delivery of a drug to a patientto help reduce or control disease symptoms. The methods of the inventionalso are suitable for use in patients in acute distress observed indisorders of the CNS. In other embodiments, the methods and particlesdisclosed herein can be used in the ongoing (non-rescue) treatment ofParkinson's disease.

[0062] In addition to Parkinson's disease, forms of epileptical seizuressuch as occurring in Myoclonic Epilepsies, including Progressive andJuvenile; Partial Epilepsies, including Complex Partial, Frontal Lobe,Motor and Sensory, Rolandic and Temporal Lobe; Benign Neonatal Epilepsy;Post-Traumatic Epilepsy; Reflex Epilepsy; Landau-Kleffner Syndrome; andSeizures, including Febrile, Status Epilepticus, and Epilepsia PartialisContinua also can be treated using the method of the invention.

[0063] Attention deficit/hyperactivity disorders (ADHD) also can betreated using the methods and formulations of the invention.

[0064] Sleep disorders that can benefit from the present inventioninclude Dyssomnias, Sleep Deprivation, Circadian Rhythm Sleep Disorders,Intrinsic Sleep Disorders, including Disorders of Excessive Somnolence,Idiopathic Hypersomnolence, Kleine-Levin Syndrome, Narcolepsy, NocturnalMyoclonus Syndrome, Restless Legs Syndrome, Sleep Apnea Syndromes, SleepInitiation and Maintenance Disorders, Parasomnias, Nocturnal NyoclonusSyndrome, Nocturnal Paroxysmal Dystonia, REM Sleep Parasomnias, SleepArousal Disorders, Sleep Bruxism, and Sleep-Wake Transition Disorders.Sleep interruption often occurs around 2 to 3 a.m. and requirestreatment the effect of which lasts approximately 3 to 4 hours.

[0065] Examples of other disorders of the central nervous system whichcan be treated by the method of the invention include but are notlimited to appetite suppression, motion sickness, panic or anxietyattack disorders, nausea suppressions, mania, bipolar disorders,schizophrenia and others, known in the art to require rescue therapy.

[0066] Medicaments which can be delivered by the method of the inventioninclude pharmaceutical preparations such as those generally prescribedin the rescue therapy of disorders of the nervous system. In a preferredembodiment, the medicament is a dopamine precursor, dopamine agonist orany combination thereof. Preferred dopamine precursors include levodopa(L-Dopa). Other drugs generally administered in the treatment ofParkinson's disease and which may be suitable in the methods of theinvention include, for example, ethosuximide, dopamine agonists such as,but not limited to carbidopa, apomorphine, sopinirole, pramipexole,pergoline, bronaocriptine. The L-Dopa or other dopamine precursor oragonist may be any form or derivative that is biologically active in thepatient being treated.

[0067] Examples of anticonvulsants include but are not limited todiazepam, valproic acid, divalproate sodium, phenytoin, phenytoinsodium, cloanazepam, primidone, phenobarbital, phenobarbital sodium,carbamazepine, amobarbital sodium, methsuximide, metharbital,mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin,phenacemide, secobarbitol sodium, clorazepate dipotassium,trimethadione. Other anticonvulsant drugs include, for example,acetazolamide, carbamazepine, chlormethiazole, clonazepam, clorazepatedipotassium, diazepam, dimethadione, estazolam, ethosuximide,flunarizine, lorazepam, magnesium sulfate, medazepam, melatonin,mephenytoin, mephobarbital, meprobamate, nitrazepam, paraldehyde,phenobarbital, phenytoin, primidone, propofol, riluzole, thiopental,tiletamine, trimethadione, valproic acid, vigabatrin. Benzodiazepinesare preferred drugs. Examples include, but are not limited to,alprazolam, chlordiazepoxide, clorazepate dipotassium, estazolam,medazepam, midazolam, triazolam, as well as benzodiazepinones, includinganthramycin, bromazepam, clonazepam, devazepide, diazepam, flumazenil,flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, pirensepine,prazepam, and temazepam.

[0068] Examples of drugs for providing symptomatic relief for migrainesinclude the non-steroidal anti-inflammatory drugs (NSAIDs). Generally,parenteral NSAIDs are more effective against migraine than oral forms.Among the various NSAIDs, ketoprofen is considered by many to be one ofthe more effective for migraine. Its Tmax via the oral route, however,is about 90 min. Other NSAIDs include aminopyrine, amodiaquine,ampyrone, antipyrine, apazone, aspirin, benzydamine, bromelains,bufexamac, BW-755C, clofazimine, clonixin, curcumin, dapsone,diclofenac, diflunisal, dipyrone, epirizole, etodolac, fenoprofen,flufenamic acid, flurbiprofen, glycyrrhizic acid, ibuprofen,indomethacin, ketorolac, ketorolac tromethamine, meclofenamic acid,mefenamic acid, mesalamine, naproxen, niflumic acid, oxyphenbutazone,pentosan sulfuric polyester, phenylbutazone, piroxicam, prenazone,salicylates, sodium salicylate, sulfasalazine, sulindac, suprofen, andtolmetin.

[0069] Other antimigraine agents include triptans, ergotamine tartrate,propanolol hydrochloride, isometheptene mucate, dichloralphenazone, andothers.

[0070] Agents administered in the treatment of ADHD include, amongothers, methylpenidate, dextroamphetamine, pemoline, imipramine,desipramine, thioridazine and carbamazepine.

[0071] Preferred drugs for sleep disorders include the benzodiazepines,for instance, alprazolam, chlordiazepoxide, clorazepate dipotassium,estazolam, medazepam, midazolam, triazolam, as well asbenzodiazepinones, including anthramycin, bromazepam, clonazepam,devazepide, diazepam, flumazenil, flunitrazepam, flurazepam, lorasepam,nitrazepam, oxazepam, pirenzepine, prazepam, temazepam, and triazolam.Another drug is zolpidem (Ambien®, Lorex) which is currently given as a5 mg tablet with T_(max)=1.6 hours; ½ Life=2.6 hours (range between 1.4to 4.5 hours). Peak plasma levels are reached in about 2 hours with ahalf-life of about 1.5 to 5.5 hours. Still another drug is triazolam(Halcion®, Pharmacia) which is a heterocyclic benzodiazepine derivativewith a molecular weight of 343 which is soluble in alcohol but poorlysoluble in water. The usual dose by mouth is 0.125 and 0.25 mg.Temazepam may be a good candidate for sleep disorders due to a longerduration of action that is sufficient to maintain sleep throughout thenight. Zaleplon (Sonata®, Wyeth Ayerst) is one drug currently approvedfor middle of night sleep restoration due to its short duration ofaction.

[0072] Other medicaments include analgesics/antipyretics for example,ketoprofen, flurbiprofen, aspirin, acetaminophen, ibuprofen, naproxensodium, buprenorphine hydrochloride, propoxyphene hydrochloride,propoxyphene napsylate, meperidine hydrochloride, hydromorphonehydrochloride, morphine sulfate, oxycodone hydrochloride, codeinephosphate, dihydrocodeine bitartrate, pentazocine hydrochloride,hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolaminesalicylate, nalbuphine hydrochloride, mefenamic acid, butorphanoltartrate, choline salicylate, butalbital, phenyltoloxamine citrate,diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride,meprobamate, and others.

[0073] Antianxiety medicaments include, for example, lorazepam,buspirone hydrochloride, prazepam, chlordizepoxide hydrochloride,oxazepam, clorazepate dipotassium, diazepam, hydroxyzine pamoate,hydroxyzine hydrochloride, alprazolam, droperidol, halazepam,chlormezanone, and others.

[0074] Examples of antipsychotic agents include haloperidol, loxapinesuccinate, loxapine hydrochloride, thioridazine, thioridazinehydrochloride, thiothixene, fluphenazine hydrochloride, fluphenazinedecanoate, fluphenazine enanthate, trifluoperazine hydrochloride,chlorpromazine hydrochloride, perphenazine, lithium citrate,prochlorperazine, and the like.

[0075] One example of an antimonic agent is lithium carbonate whileexamples of Alzheimer agents include tetra amino acridine, donapezel,and others.

[0076] Sedatives/hypnotics include barbiturates (e.g., pentobarbital,phenobarbital sodium, secobarbital sodium), benzodiazepines (e.g.,flurazepam hydrochloride, triazolam, tomazeparm, midazolamhydrochloride), and others.

[0077] Hypoglycemic agents include, for example, ondansetron,granisetron, meclizine hydrochloride, nabilone, prochlorperazine,dimenhydrinate, promethazine hydrochloride, thiethylperazine,scopolamine, and others. Antimotion sickness agents include, forexample, cinnorizine.

[0078] Combinations of drugs also can be employed.

[0079] In one embodiment of the invention the particles consist of amedicament, such as, for example, one of the medicaments describedabove. In another embodiment, the particles include one or moreadditional components. The amount of drug or medicament present in theseparticles can range 1.0 to about 90.0 weight percent.

[0080] For rescue therapy, particles that include one or morecomponent(s) which promote(s) the fast release of the medicament intothe blood stream are preferred. As used herein, rapid release of themedicament into the blood stream refers to release kinetics that aresuitable for providing rescue therapy. In one embodiment, optimaltherapeutic plasma concentration is achieved in less than 10 minutes. Itcan be achieved in as fast as about 2 minutes and even less. Optimaltherapeutic concentration often can be achieved in a time frame similaror approaching that observed with intravenous administration. Generally,optimal therapeutic plasma concentration is achieved significantlyfaster than that possible with oral administration, for example, 2 to 10times faster.

[0081] In a preferred embodiment, the particles include one or morephospholipids, such as, for example, a phosphatidylcholine,phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine,phosphatidylinositol or a combination thereof. In one embodiment, thephospholipids are endogenous to the lung. Combinations of phospholipidscan also be employed. Specific examples of phospholipids are shown inTable 1. TABLE 1 Dilaurylolyphosphatidylcholine (C12; 0) DLPCDimyristoylphosphatidylcholine (C14; 0) DMPCDipalmitoylphosphatidylcholine (C16:0) DPPCDistearoylphosphatidylcholine (18:0) DSPC Dioleoylphosphatidylcholine(C18:1) DOPC Dilaurylolylphosphatidylglycerol DLPGDimyristoylphosphatidylglycerol DMPG DipalmitoylphosphatidylglycerolDPPG Distearoylphosphatidylglycerol DSPG DioleoylphosphatidylglycerolDOPG Dimyristoyl phosphatidic acid DMPA Dimyristoyl phosphatidic acidDMPA Dipalmitoyl phosphatidic acid DPPA Dipalmitoyl phosphatidic acidDPPA Dimyristoyl phosphatidylethanolamine DMPE Dipalmitoylphosphatidylethanolamine DPPE Dimyristoyl phosphatidylserine DMPSDipalmitoyl phosphatidylserine DPPS Dipalmitoyl sphingomyelin DPSPDistearoyl sphingomyelin DSSP

[0082] The phospholipid can be present in the particles in an amountranging from about 0 to about 90 weight %. Preferably, it can be presentin the particles in an amount ranging from about 10 to about 60 weight%.

[0083] The phospholipids or combinations thereof can be selected toimpart control release properties to the particles. Particles havingcontrolled release properties and methods of modulating release of abiologically active agent are described in U.S. Provisional PatentApplication Ser. No. 60/150,742 entitled Modulation of Release From DryPowder Formulations by Controlling Matrix Transition, filed on Aug. 25,1999, U.S. Non-Provisional patent application Ser. No. 09/644,736, filedon Aug. 23, 2000, with the title Modulation of Release From Dry PowderFormulations and U.S. Non-Provisional patent ppplication Ser. No.09/792,869 filed on Feb. 23, 2001, under Attorney Docket No.2685.1012-004, and with the title Modulation of Release From Dry PowderFormulations. The contents of all three applications are incorporatedherein by reference in their entirety. Rapid release, preferred in thedelivery of a rescue therapy medicament, can be obtained for example, byincluding in the particles phospholipids characterized by low transitiontemperatures. In another embodiment, a combination of rapid withcontrolled release particles would allow a rescue therapy coupled with amore sustained release in a single cause of therapy. Control releaseproperties can be utilized in non-rescue, ongoing treatment of adisorder of the CNS.

[0084] In another embodiment of the invention the particles can includea surfactant. As used herein, the term “surfactant” refers to any agentwhich preferentially absorbs to an interface between two immisciblephases, such as the interface between water and an organic polymersolution, a water/air interface or organic solvent/air interface.Surfactants generally possess a hydrophilic moiety and a lipophilicmoiety, such that, upon absorbing to microparticles, they tend topresent moieties to the external environment that do not attractsimilarly-coated particles, thus reducing particle agglomeration.Surfactants may also promote absorption of a therapeutic or diagnosticagent and increase bioavailability of the agent.

[0085] In addition to lung surfactants, such as, for example,phospholipids discussed above, suitable surfactants include but are notlimited to hexadecanol; fatty alcohols such as polyethylene glycol(PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, suchas palmitic acid or oleic acid; glycocholate; surfactin; a poloxomer; asorbitan fatty acid ester such as sorbitan trioleate (Span 85); andtyloxapol.

[0086] The surfactant can be present in the particles in an amountranging from about 0 to about 90 weight %. Preferably, it can be presentin the particles in an amount ranging from about 10 to about 60 weight%.

[0087] Methods of preparing and administering particles includingsurfactants, and, in particular phospholipids, are disclosed in U.S.Pat. No 5,855,913, issued on Jan. 5, 1999 to Hanes et al. and in U.S.Pat. No. 5,985,309, issued on Nov. 16, 1999 to Edwards et al. Theteachings of both are incorporated herein by reference in theirentirety.

[0088] In another embodiment of the invention, the particles include anamino acid. Hydrophobic amino acids are preferred. Suitable amino acidsinclude naturally occurring and non-naturally occurring hydrophobicamino acids. Examples of amino acids which can be employed include, butare not limited to: glycine, proline, alanine, cysteine, methionine,valine, leucine, tyrosine, isoleucine, phenylalanine, tryptophan.Preferred hydrophobic amino acids, include but are not limited to,leucine, isoleucine, alanine, valine, phenylalanine, glycine andtryptophan. Amino acids include combinations of hydrophobic amino acidscan also be employed. Non-naturally occurring amino acids include, forexample, beta-amino acids. Both D, L and racemic configurations ofhydrophobic amino acids can be employed. Suitable hydrophobic aminoacids can also include amino acid analogs. As used herein, an amino acidanalog includes the D or L configuration of an amino acid having thefollowing formula: —NH—CHR—CO—, wherein R is an aliphatic group, asubstituted aliphatic group, a benzyl group, a substituted benzyl group,an aromatic group or a substituted aromatic group and wherein R does notcorrespond to the side chain of a naturally-occurring amino acid. Asused herein, aliphatic groups include straight chained, branched orcyclic Cl—C8 hydrocarbons which are completely saturated, which containone or two heteroatoms such as nitrogen, oxygen or sulfur and/or whichcontain one or more units of unsaturation. Aromatic groups includecarbocyclic aromatic groups such as phenyl and naphthyl and heterocyclicaromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl,pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyland acridintyl.

[0089] Suitable substituents on an aliphatic, aromatic or benzyl groupinclude —OH, halogen (—Br, —Cl, —I and —F) —O(aliphatic, substitutedaliphatic, benzyl, substituted benzyl, aryl or substituted aryl group),—CN, —NO₂, —COOH, —NH₂, —NH(aliphatic group, substituted aliphatic,benzyl, substituted benzyl, aryl or substituted aryl group),—N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl,aryl or substituted aryl group)₂, —COO(aliphatic group, substitutedaliphatic, benzyl, substituted benzyl, aryl or substituted aryl group),—CONH₂, —CONH(aliphatic, substituted aliphatic group, benzyl,substituted benzyl, aryl or substituted aryl group)), —SH, —S(aliphatic,substituted aliphatic, benzyl, substituted benzyl, aromatic orsubstituted aromatic group) and —NH—C(═NH)—NH₂. A substituted benzylicor aromatic group can also have an aliphatic or substituted aliphaticgroup as a substituent. A substituted aliphatic group can also have abenzyl, substituted benzyl, aryl or substituted aryl group as asubstituent. A substituted aliphatic, substituted aromatic orsubstituted benzyl group can have one or more substituents. Modifying anamino acid substituent can increase, for example, the lypophilicity orhydrophobicity of natural amino acids which are hydrophillic.

[0090] A number of the suitable amino acids, amino acids analogs andsalts thereof can be obtained commercially. Others can be synthesized bymethods known in the art. Synthetic techniques are described, forexample, in Green and Wuts, “Protecting Groups in Organic Synthesis”,John Wiley and Sons, Chapters 5 and 7, 1991.

[0091] Hydrophobicity is generally defined with respect to the partitionof an amino acid between a nonpolar solvent and water. Hydrophobic aminoacids are those acids which show a preference for the nonpolar solvent.Relative hydrophobicity of amino acids can be expressed on ahydrophobicity scale on which glycine has the value 0.5. On such ascale, amino acids which have a preference for water have values below0.5 and those that have a preference for nonpolar solvents have a valueabove 0.5. As used herein, the term hydrophobic amino acid refers to anamino acid that, on the hydrophobicity scale has a value greater orequal to 0.5, in other words, has a tendency to partition in thenonpolar acid which is at least equal to that of glycine.

[0092] Combinations of hydrophobic amino acids can also be employed.Furthermore, combinations of hydrophobic and hydrophilic (preferentiallypartitioning in water) amino acids, where the overall combination ishydrophobic, can also be employed. Combinations of one or more aminoacids and one or more phospholipids or surfactants can also be employed.Materials which impart fast release kinetics to the medicament arepreferred.

[0093] The amino acid can be present in the particles of the inventionin an amount of at least 10 weight %. Preferably, the amino acid can bepresent in the particles in an amount ranging from about 20 to about 80weight %. The salt of a hydrophobic amino acid can be present in theparticles of the invention in an amount of at least 10% weight.Preferably, the amino acid salt is present in the particles in an amountranging from about 20 to about 80 weight %. Methods of forming anddelivering particles which include an amino acid are described in U.S.patent application Ser. No 09/382,959, filed on Aug. 25, 1999, entitledUse of Simple Amino Acids to Form Porous Particles During Spray Dryingand in U.S. Non-Provisional patent application Ser. No. 09/644,320,filed on Aug. 23, 2000, titled Use of Simple Amino Acids to Form PorousParticles, the teachings of both are incorporated herein by reference intheir entirety.

[0094] In another embodiment of the invention, the particles include acarboxylate moiety and a multivalent metal salt. One or morephospholipids also can be included. Such compositions are described inU.S. Provisional Application 60/150,662, filed on Aug. 25, 1999,entitled Formulation for Spray-Drying Large Porous Particles, and U.S.Non-Provisional patent application Ser. No. 09/644,105, filed on Aug.23, 2000, titled Formulation for Spray-Drying Large Porous Particles,the teachings of both are incorporated herein by reference in theirentirety. In a preferred embodiment, the particles include sodiumcitrate and calcium chloride.

[0095] Other materials, preferably materials which promote fast releasekinetics of the medicament can also be employed. For example,biocompatible, and preferably biodegradable polymers can be employed.Particles including such polymeric materials are described in U.S. Pat.No. 5,874,064, issued on Feb. 23, 1999 to Edwards et al., the teachingsof which are incorporated herein by reference in their entirety.

[0096] The particles can also include a material such as, for example,dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins,peptides, polypeptides, fatty acids, inorganic compounds, phosphates.

[0097] In one specific example, the particles include (by weightpercent) 50% L-Dopa, 25% DPPC, 15% sodium citrate and 10% calciumchloride. In another specific example, the particles include (by weightpercent) 50% L-Dopa, 40% leucine and 10% sucrose. In yet anotherembodiment the particles include (by weight percent) 10% benzodiazepine,20% sodium citrate, 10% calcium chloride and 60% DPPC.

[0098] In a preferred embodiment, the particles of the invention have atap density less than about 0.4 g/cm³. Particles which have a tapdensity of less than about 0.4 g/cm³ are referred herein as“aerodynamically light particles”. More preferred are particles having atap density less than about 0.1 g/cm³. Tap density can be measured byusing instruments known to those skilled in the art such as but notlimited to the Dual Platform Microprocessor Controlled Tap DensityTester (Vankel, N.C.) or a GeoPyc™ instrument (Micrometrics InstrumentCorp., Norcross, Ga. 30093). Tap density is a standard measure of theenvelope mass density. Tap density can be determined using the method ofUSP Bulk Density and Tapped Density, United States Pharmacopeiaconvention, Rockville, Md., 10^(th) Supplement, 4950-4951, 1999.Features which can contribute to low tap density include irregularsurface texture and porous structure.

[0099] The envelope mass density of an isotropic particle is defined asthe mass of the particle divided by the minimum sphere envelope volumewithin which it can be enclosed. In one embodiment of the invention, theparticles have an envelope mass density of less than about 0.4 g/cm³.

[0100] Aerodynamically light particles have a preferred size, e.g., avolume median geometric diameter (VMGD) of at least about 5 microns(μm). In one embodiment, the VMGD is from about 5 μm to about 30 μm. Inanother embodiment of the invention, the particles have a VMGD rangingfrom about 10 μm to about 30 μm. In other embodiments, the particleshave a median diameter, mass median diameter (MMD), a mass medianenvelope diameter (MMED) or a mass median geometric diameter (MMGD) ofat least 5 μm, for example from about 5 μm and about 30 μm.

[0101] The diameter of the spray-dried particles, for example, the VMGD,can be measured using an electrical zone sensing instrument such as aMultisizer IIe, (Coulter Electronic, Luton, Beds, England), or a laserdiffraction instrument (for example Helos, manufactured by Sympatec,Princeton, N.J.). Other instruments for measuring particle diameter arewell known in the art. The diameter of particles in a sample will rangedepending upon factors such as particle composition and methods ofsynthesis. The distribution of size of particles in a sample can beselected to permit optimal deposition to targeted sites within therespiratory tract.

[0102] Aerodynamically light particles preferably have “mass medianaerodynamic diameter” (MMAD), also referred to herein as “aerodynamicdiameter”, between about 1 μm and about 5 μm. In another embodiment ofthe invention, the MMAD is between about 1 μm and about 3 μm. In afurther embodiment, the MMAD is between about 3 μm and about 5 μm.

[0103] Experimentally, aerodynamic diameter can be determined byemploying a gravitational settling method, whereby the time for anensemble of particles to settle a certain distance is used to inferdirectly the aerodynamic diameter of the particles. An indirect methodfor measuring the mass median aerodynamic diameter (MMAD) is themulti-stage liquid impinger (MSLI).

[0104] The aerodynamic diameter, daer, can be calculated from theequation:

d _(aer) =d _(g){square root}ρ_(tap)

[0105] where d_(g) is the geometric diameter, for example the MMGD, andρ is the powder density.

[0106] Particles which have a tap density less than about 0.4 g/cm³,median diameters of at least about 5 μm, and an aerodynamic diameter ofbetween about 1 μm and about 5 μm, preferably between about 1 μm andabout 3 μm, are more capable of escaping inertial and gravitationaldeposition in the oropharyngeal region, and are targeted to the airways,particularly the deep lung. The use of larger, more porous particles isadvantageous since they are able to aerosolize more efficiently thansmaller, denser aerosol particles such as those currently used forinhalation therapies.

[0107] In comparison to smaller, relatively denser particles the largeraerodynamically light particles, preferably having a median diameter ofat least about 5 μm, also can potentially more successfully avoidphagocytic engulfment by alveolar macrophages and clearance from thelungs, due to size exclusion of the particles from the phagocytescytosolic space. Phagocytosis of particles by alveolar macrophagesdiminishes precipitously as particle diameter increases beyond about 3μm. Kawaguchi, H., et al., Biomaterials7: 61-66 (1986); Krenis, L. J.and Strauss, B., Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S.and Muller, R. H., J Contr. Rel., 22: 263-272 (1992). For particles ofstatistically isotropic shape, such as spheres with rough surfaces, theparticle envelope volume is approximately equivalent to the volume ofcytosolic space required within a macrophage for complete particlephagocytosis.

[0108] The particles may be fabricated with the appropriate material,surface roughness, diameter and tap density for localized delivery toselected regions of the respiratory tract such as the deep lung or upperor central airways. For example, higher density or larger particles maybe used for upper airway delivery, or a mixture of varying sizedparticles in a sample, provided with the same or different therapeuticagent may be administered to target different regions of the lung in oneadministration. Particles having an aerodynamic diameter ranging fromabout 3 to about 5 μm are preferred for delivery to the central andupper airways. Particles having and aerodynamic diameter ranging fromabout 1 to about 3 μm are preferred for delivery to the deep lung.Inertial impaction and gravitational settling of aerosols arepredominant deposition mechanisms in the airways and acini of the lungsduring normal breathing conditions. Edwards, D. A., J Aerosol Sci., 26:293-317 (1995). The importance of both deposition mechanisms increasesin proportion to the mass of aerosols and not to particle (or envelope)volume. Since the site of aerosol deposition in the lungs is determinedby the mass of the aerosol (at least for particles of mean aerodynamicdiameter greater than approximately 1 μm), diminishing the tap densityby increasing particle surface irregularities and particle porositypermits the delivery of larger particle envelope volumes into the lungs,all other physical parameters being equal.

[0109] The low tap density particles have a small aerodynamic diameterin comparison to the actual envelope sphere diameter. The aerodynamicdiameter, d_(aer), is related to the envelope sphere diameter, d (Gonda,I., “Physico-chemical principles in aerosol delivery,” in Topics inPharmaceutical Sciences 1991 (eds. D. J. A. Crommelin and K. K. Midha),pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)), by theformula:

d _(aer) =d{square root}ρ

[0110] where the envelope mass ρ is in units of g/cm³. Maximaldeposition of monodispersed aerosol particles in the alveolar region ofthe human lung (˜60%) occurs for an aerodynamic diameter ofapproximately d_(aer)=3 μm. Heyder, J. et al., J Aerosol Sci., 17:811-825 (1986). Due to their small envelope mass density, the actualdiameter d of aerodynamically light particles comprising a monodisperseinhaled powder that will exhibit maximum deep-lung deposition is:

d=3/{square root}ρμm (where ρ<1 g/cm³);

[0111] where d is always greater than 3 μm. For example, aerodynamicallylight particles that display an envelope mass density, ρ=0.1 g/cm³, willexhibit a maximum deposition for particles having envelope diameters aslarge as 9.5 μm. The increased particle size diminishes interparticleadhesion forces. Visser, J., Powder Technology, 58: 1-10. Thus, largeparticle size increases efficiency of aerosolization to the deep lungfor particles of low envelope mass density, in addition to contributingto lower phagocytic losses.

[0112] The aerodynamic diameter can be calculated to provide for maximumdeposition within the lungs. Previously this was achieved by the use ofvery small particles of less than about five microns in diameter,preferably between about one and about three microns, which are thensubject to phagocytosis. Selection of particles which have a largerdiameter, but which are sufficiently light (hence the characterization“aerodynamically light”), results in an equivalent delivery to thelungs, but the larger size particles are not phagocytosed. Improveddelivery can be obtained by using particles with a rough or unevensurface relative to those with a smooth surface. In another embodimentof the invention, the particles have an envelope mass density, alsoreferred to herein as “mass density” of less than about 0.4 g/cm³.Particles also having a mean diameter of between about 5 μm and about 30μm are preferred. Mass density and the relationship between massdensity, mean diameter and aerodynamic diameter are discussed in U.S.application Ser. No. 08/655,570, filed on May 24, 1996, which isincorporated herein by reference in its entirety. In a preferredembodiment, the aerodynamic diameter of particles having a mass densityless than about 0.4 g/cm³ and a mean diameter of between about 5 μm andabout 30 μm mass mean aerodynamic diameter is between about 1 μm andabout 5 μm.

[0113] Suitable particles can be fabricated or separated, for example byfiltration or centrifugation, to provide a particle sample with apreselected size distribution. For example, greater than about 30%, 50%,70%, or 80% of the particles in a sample can have a diameter within aselected range of at least about 5 μm. The selected range within which acertain percentage of the particles must fall may be for example,between about 5 and about 30 μm, or optimally between about 5 and about15 μm. In one preferred embodiment, at least a portion of the particleshave a diameter between about 9 and about 11 μm. Optionally, theparticle sample also can be fabricated wherein at least about 90%, oroptionally about 95% or about 99%, have a diameter within the selectedrange. The presence of the higher proportion of the aerodynamicallylight, larger diameter particles in the particle sample enhances thedelivery of therapeutic or diagnostic agents incorporated therein to thedeep lung. Large diameter particles generally mean particles having amedian geometric diameter of at least about 5 μm.

[0114] In a preferred embodiment, suitable particles which can beemployed in the method of the invention are fabricated by spray drying.In one embodiment, the method includes forming a mixture includingL-Dopa or another medicament, or a combination thereof, and asurfactant, such as, for example, the surfactants described above. In apreferred embodiment, the mixture includes a phospholipid, such as, forexample the phospholipids described above. The mixture employed in spraydrying can include an organic or aqueous-organic solvent.

[0115] Suitable organic solvents that can be employed include but arenot limited to alcohols for example, ethanol, methanol, propanol,isopropanol, butanols, and others. Other organic solvents include butare not limited to perfluorocarbons, dichloromethane, chloroform, ether,ethyl acetate, methyl tert-butyl ether and others. Co-solvents includean aqueous solvent and an organic solvent, such as, but not limited to,the organic solvents as described above. Aqueous solvents include waterand buffered solutions. In one embodiment, an ethanol water solvent ispreferred with the ethanol:water ratio ranging from about 50:50 to about90:10 ethanol:water.

[0116] The spray drying mixture can have a neutral, acidic or alkalinepH. Optionally, a pH buffer can be added to the solvent or co-solvent orto the formed mixture. Preferably, the pH can range from about 3 toabout 10.

[0117] Suitable spray-drying techniques are described, for example, byK. Masters in “Spray Drying Handbook”, John Wiley & Sons, New York,1984. Generally, during spray-drying, heat from a hot gas such as heatedair or nitrogen is used to evaporate the solvent from droplets formed byatomizing a continuous liquid feed. Other spray-drying techniques arewell known to those skilled in the art. In a preferred embodiment, arotary atomizer is employed. An example of suitable spray driers usingrotary atomization includes the Mobile Minor spray drier, manufacturedby Niro, Denmark. The hot gas can be, for example, air, nitrogen orargon. In a specific example, 250 milligrams (mg) of L-Dopa in 700milliliters (ml) of ethanol are combined with 300 ml of water containing500 mg L-Dopa, 150 mg sodium citrate and 100 mg calcium chloride and theresulting mixture is spray dried. In another example, 700 ml of watercontaining 500 mg L-Dopa, 100 sucrose and 400 mg leucine are combinedwith 300 ml of ethanol and the resulting mixture is spray dried.

[0118] The particles can be fabricated with a rough surface texture toreduce particle agglomeration and improve flowability of the powder. Thespray-dried particles have improved aerosolization properties. Thespray-dried particle can be fabricated with features which enhanceaerosolization via dry powder inhaler devices, and lead to lowerdeposition in the mouth, throat and inhaler device. The particles of theinvention can be employed in compositions suitable for drug delivery tothe pulmonary system. For example, such compositions can include theparticles and a pharmaceutically acceptable carrier for administrationto a patient, preferably for administration via inhalation. Theparticles may be administered alone or in any appropriatepharmaceutically acceptable carrier, such as a liquid, for examplesaline, or a powder, for administration to the respiratory system. Theycan be co-delivered with larger carrier particles, not including atherapeutic agent, the latter possessing mass median diameters forexample in the range between about 50 μm and about 100 μm.

[0119] Aerosol dosage, formulations and delivery systems may be selectedfor a particular therapeutic application, as described, for example, inGonda, I. “Aerosols for delivery of therapeutic and diagnostic agents tothe respiratory tract,” in Critical Reviews in Therapeutic Drug CarrierSystems, 6: 273-313, 1990; and in Moren, “Aerosol dosage forms andformulations,” in: Aerosols in Medicine. Principles, Diagnosis andTherapy, Moren, et al., Eds, Esevier, Amsterdam, 1985.

[0120] The method of the invention includes delivering to the pulmonarysystem an effective amount of a medicament such as, for example, amedicament described above. As used herein, the term “effective amount”means the amount needed to achieve the desired effect or efficacy. Theactual effective amounts of drug can vary according to the specific drugor combination thereof being utilized, the particular compositionformulated, the mode of administration, and the age, weight, conditionof the patient, and severity of the episode being treated. In rescuetherapy, the effective amount refers to the amount needed to achieveabatement of symptoms or cessation of the episode. In the case of adopamine precursor, agonist or combination thereof it is an amount whichreduces the Parkinson's symptoms which require rescue therapy. Dosagesfor a particular patient are described herein and can be determined byone of ordinary skill in the art using conventional considerations,(e.g. by means of an appropriate, conventional pharmacologicalprotocol). For example, effective amounts of oral L-Dopa range fromabout 50 milligrams (mg) to about 500 mg. In many instances, a commonongoing (oral) L-Dopa treatment schedule is 100 mg eight (8) times aday. During rescue therapy, effective doses of oral L-Dopa generally aresimilar to those administered in the ongoing treatment.

[0121] For being effective during rescue therapy, plasma levels ofL-dopa generally are similar to those targeted during ongoing(non-rescue therapy) L-Dopa treatment. Effective amounts of L-Dopagenerally result in plasma blood concentrations that range from about0.5 microgram μg)/liter(l) to about 2.0 μg/l.

[0122] It has been discovered in this invention that pulmonary deliveryof L-Dopa doses, when normalized for body weight, result in at least a2-fold increase in plasma level as well as in therapeutical advantagesin comparison with oral administration. Significantly higher plasmalevels and therapeutic advantages are possible in comparison with oraladministration. In one example, pulmonary delivery of L-Dopa results ina plasma level increase ranging from about 2-fold to about 10-fold whencompared to oral administration. Plasma levels that approach or aresimilar to those obtained with intravenous administration can beobtained. Similar findings were made with other drugs suitable intreating disorders of the CNS, such as, for example, ketoprofen.

[0123] Assuming that bioavailability remains the same as dosage isincreased, the amount of oral drug, e.g. L-Dopa, ketoprofen, required toachieve plasma levels comparable to those resulting from pulmonarydelivery by the methods of the invention can be determined at a givenpoint after administration. In a specific example, the plasma levels 2minutes after oral and administration by the methods of the invention,respectively, are 1 μg/ml L-Dopa and 5 μg/ml L-Dopa. Thus 5 times theoral dose would be needed to achieve the 5 μg/ml level obtained byadministering the drug using the methods of the invention. In anotherexample, the L-Dopa plasma levels at 120 minutes after administrationare twice as high with the methods of the invention when compared tooral administration. Thus twice as much L-Dopa is required afteradministration 1 μg/ml following oral administration in comparison tothe amount administered using the methods of the invention.

[0124] To obtain a given drug plasma concentration, at a given timeafter administration, less drug is required when the drug is deliveredby the methods of the invention than when it is administered orally.Generally, at least a two-fold dose reduction can be employed in themethods of the invention in comparison to the dose used in conventionaloral administration. A much higher dose reduction is possible. In oneembodiment of the invention, a five fold reduction in dose is employedand reductions as high as about ten fold can be used in comparison tothe oral dose.

[0125] At least a two-fold dose reduction also is employed in comparisonto other routes of administration, other than intravenous, such as, forexample, intramuscular, subcutaneous, buccal, nasal, intra-peritoneal,rectal.

[0126] In addition or alternatively to the pharmacokinetic effect,(e.g., serum level, dose advantage) described above, the dose advantageresulting from the pulmonary delivery of a drug, e.g., L-Dopa, used totreat disorders of the CNS, also can be described in terms of apharmacodynamic response. Compared to the oral route, the methods of theinvention avoid inconsistent medicament uptake by intestines, avoidanceof delayed uptake following eating, avoidance of first pass catabolismof the drug in the circulation and rapid delivery from lung to brain viaaortic artery.

[0127] As discussed above, rapid delivery to the medicament's site ofaction often is desired. Preferably, the effective amount is deliveredon the “first pass” of the blood to the site of action. The “first pass”is the first time the blood carries the drug to and within the targetorgan from the point at which the drug passes from the lung to thevascular system. Generally, the medicament is released in the bloodstream and delivered to its site of action within a time period which issufficiently short to provide rescue therapy to the patient beingtreated. In many cases, the medicament can reach the central nervoussystem in less than about 10 minutes, often as quickly as two minutesand even faster.

[0128] Preferably, the patient's symptoms abate within minutes andgenerally no later than one hour. In one embodiment of the invention,the release kinetics of the medicament are substantially similar to thedrug's kinetics achieved via the intravenous route. In anotherembodiment of the invention, the T_(max) of the medicament in the bloodstream ranges from about 1 to about 10 minutes. As used herein, the termT_(max) means the point at which levels reach a maximum concentration.In many cases, the onset of treatment obtained by using the methods ofthe invention is at least two times faster than onset of treatmentobtained with oral delivery. Significantly faster treatment onset can beobtained. In one example, treatment onset is from about 2 to about 10times faster than that observed with oral administration.

[0129] If desired, particles which have fast release kinetics, suitablein rescue therapy, can be combined with particles having sustainedrelease, suitable in treating the chronic aspects of a condition. Forexample, in the case of Parkinson's disease, particles designed toprovide rescue therapy can be co-administered with particles havingcontrolled release properties.

[0130] The administration of more than one dopamine precursor, agonistor combination thereof, in particular L-Dopa, carbidopa, apomorphine,and other drugs can be provided, either simultaneously or sequentiallyin time. Carbidopa, for example, is often administered to ensure thatperipheral carboxylase activity is completely shut down. Intramuscular,subcutaneous, oral and other administration routes can be employed. Inone embodiment, these other agents are delivered to the pulmonarysystem. These compounds or compositions can be administered before,after or at the same time. In a preferred embodiment, particles that areadministered to the respiratory tract include both L-Dopa and carbidopa.The term “co-administration” is used herein to mean that the specificdopamine precursor, agonist or combination thereof and/or othercompositions are administered at times to treat the episodes, as well asthe underlying conditions described herein.

[0131] In one embodiment regular chronic (non-rescue) L-Dopa therapyincludes pulmonary delivery of L-Dopa combined with oral carbidopa. Inanother embodiment, pulmonary delivery of L-Dopa is provided during theepisode, while chronic treatment can employ conventional oraladministration of L-Dopa/carbidopa.

[0132] Preferably, particles administered to the respiratory tracttravel through the upper airways (oropharynx and larynx), the lowerairways which include the trachea followed by bifurcations into thebronchi and bronchioli and through the terminal bronchioli which in turndivide into respiratory bronchioli leading then to the ultimaterespiratory zone, the alveoli or the deep lung. In a preferredembodiment of the invention, most of the mass of particles deposits inthe deep lung or alveoli.

[0133] Administration of particles to the respiratory system can be bymeans such as known in the art. For example, particles are deliveredfrom an inhalation device. In a preferred embodiment, particles areadministered via a dry powder inhaler (DPI). Metered-dose-inhalers(MDI), nebulizers or instillation techniques also can be employed.

[0134] Various suitable devices and methods of inhalation which can beused to administer particles to a patient's respiratory tract are knownin the art. For example, suitable inhalers are described in U.S. Pat.No. 4,069,819, issued Aug. 5, 1976 to Valentini, et al., U.S. Pat. No.4,995,385 issued Feb. 26, 1991 to Valentini, et al., and U.S. Pat. No.5,997,848 issued Dec. 7, 1999 to Patton, et al. Other examples include,but are not limited to, the Spinhaler® (Fisons, Loughborough, U.K.),Rotahaler® (Glaxo-Wellcome, Research Triangle Technology Park, N.C.),FlowCaps® (Hovione, Loures, Portugal), Inhalator® (Boehringer-Ingelheim,Germany), and the Aerolizer® (Novartis, Switzerland), the diskhaler(Glaxo-Wellcome, RTP, NC) and others, such as known to those skilled inthe art. In one embodiment, the inhaler employed is described in U.S.Patent Application, entitled Inhalation Device and Method, by David A.Edwards, et al., filed on Apr. 16, 2001, under Attorney Docket No.00166.0109.US00. The entire contents of this application areincorporated by reference herein.

[0135] The invention further is related to methods for administering tothe pulmonary system a therapeutic dose of the medicament in a smallnumber of steps, and preferably in a single, breath activated step. Theinvention also is related to methods of delivering a therapeutic dose ofa drug to the pulmonary system, in a small number of breaths, andpreferably in one or two single breaths. The methods includesadministering particles from a receptacle having, holding, containing,storing or enclosing a mass of particles, to a subject's respiratorytract.

[0136] In one embodiment of the invention, delivery to the pulmonarysystem of particles is by the methods described in U.S. PatentApplication, High Efficient Delivery of a Large Therapeutic MassAerosol, application Ser. No. 09/591,307, filed Jun. 9, 2000, and thosedescribed in the Continuation-in-Part of U.S. application Ser. No.09/591,307, which is filed concurrently herewith, under Attorney Docketnumber 2685.2001-003. The entire contents of both these applications areincorporated herein by reference. As disclosed therein, particles areheld, contained, stored or enclosed in a receptacle. Preferably, thereceptacle, e.g. capsule or blister, has a volume of at least about 0.37cm³ and can have a design suitable for use in a dry powder inhaler.Larger receptacles having a volume of at least about 0.48 cm³, 0.67 cm³or 0.95 cm³ also can be employed.

[0137] In one example, at least 50% of the mass of the particles storedin the inhaler receptacle is delivered to a subject's respiratory systemin a single, breath-activated step. In another embodiment, at least 10milligrams of the medicament is delivered by administering, in a singlebreath, to a subject's respiratory tract particles enclosed in thereceptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligramscan be delivered.

[0138] In one embodiment, delivery to the pulmonary system of particlesin a single, breath-actuated step is enhanced by employing particleswhich are dispersed at relatively low energies, such as, for example, atenergies typically supplied by a subject's inhalation. Such energies arereferred to herein as “low.” As used herein, “low energy administration”refers to administration wherein the energy applied to disperse and/orinhale the particles is in the range typically supplied by a subjectduring inhaling.

[0139] The invention also is related to methods for efficientlydelivering powder particles to the pulmonary system. In one embodimentof the invention, at least about 70% and preferably at least about 80%of the nominal powder dose is actually delivered. As used herein, theterm “nominal powder dose” is the total amount of powder held in areceptacle, such as employed in an inhalation device. As used herein,the term nominal drug dose is the total amount of medicament containedin the nominal amount of powder. The nominal powder dose is related tothe nominal drug dose by the load percent of drug in the powder.

[0140] In a specific example, dry powder from a dry powder inhalerreceptacle, e.g., capsule, holding 25 mg nominal powder dose having at50% L-Dopa load, i.e., 12,5 mg L-Dopa, is administered in a singlebreath. Based on a conservative 4-fold dose advantage, the 12,5 mgdelivered in one breath are the equivalent of about 50 mg of L-Doparequired in oral administration. Several such capsules can be employedto deliver higher doses of L-Dopa. For instance a size 4 capsule can beused to deliver 50 mg of 1-Dopa to the pulmonary system to replace(considering the same conservative 4-fold dose advantage) a 200 mg oraldose.

[0141] Properties of the particles enable delivery to patients withhighly compromised lungs where other particles prove ineffective forthose lacking the capacity to strongly inhale, such as young patients,old patients, infirm patients, or patients with asthma or otherbreathing difficulties. Further, patients suffering from a combinationof ailments may simply lack the ability to sufficiently inhale. Thus,using the methods and particles for the invention, even a weakinhalation is sufficient to deliver the desired dose. This isparticularly important when using the particles of the instant inventionas rescue therapy for a patient suffering from debilitating illness ofthe central nervous system for example but not limited to migraine,anxiety, psychosis, depression, bipolar disorder, obsessive compulsivedisorder (OCD), convulsions, seizures, epilepsy, Alzheimer's, andespecially, Parkinson's disease.

[0142] The present invention will be further understood by reference tothe following non-limiting examples.

EXEMPLIFICATIONS Example 1

[0143] In vivo tests were performed to compare oral and trachealadministration of L-Dopa in a rat model. Animals received an IPinjection of the peripheral decarboxylase inhibitor carbidopa (Sigma,St. Louis, Mo.) (200 mg/kg) one hour prior to administration of L-Dopa.Under ketamine anesthesia, the animals were divided into two groups. Inthe first group of animals (N=4), L-Dopa (8 mg) was suspended in salinecontaining 2% methylcellulose and given via oral gavage. In the secondgroup (N=5) a small tracheotomy was performed to permit placement of apipette tip with a modified 2 mm opening through the trachea and intothe lungs. The pipette tip was pre-loaded with powdered L-Dopa (8 mg)and was interfaced with an oxygen tank using silicone tubing. Coincidingwith the respiratory cycle of the animal, L-Dopa was pushed into thelungs using a burst of oxygen (5 liters/minute). Blood samples (200 μl)were withdrawn from a previously placed femoral cannula at the followingtime points: 0 (immediately prior to L-Dopa administration), 1, 5, 15,30, 45 and 60 minutes following L-Dopa administration.

[0144] Blood levels of L-Dopa, measured, respectively, by massspectrometry or HPLC, following administration via oral gavage or directadministration into the lungs are shown in FIGS. 1A and 1B. The increasein blood levels of L-Dopa over time following oral administration wasmodest. In contrast, administration into the lungs produced a robust andrapid rise in L-Dopa levels which peaked between 1 and 5 minutes postdrug administration. L-Dopa levels in this group decreased between 5 and15 minutes and remained stable thereafter. Data are presented as themean ±SEM ng L-Dopa level/ml blood.

[0145] Relationship between blood L-Dopa levels and striatal dopaminelevels following delivery of L-Dopa either orally or directly into thelungs, as described above, are shown in FIGS. 2A and 2B. FIG. 2A showsblood L-Dopa levels immediately prior to L-Dopa (baseline) and at 2, 15and 45 minutes following L-Dopa (N=4-6 per time point for each group).Once again, the levels following administration into the lungs show arobust and rapid increase in L-Dopa levels, relative to the modestincreases following oral administration.

[0146]FIG. 2B shows dopamine levels in the striatum from the sameanimals shown in FIG. 2A. Immediately following withdrawal of the bloodsample, the brains were removed and striatum dissected free. Tissuelevels of dopamine were determined using high performance liquidchromatography (HPLC). Note that the marked difference in blood L-Dopalevels seen between the two treatments at two minutes was followed,later in time, by more modest but significant differences in striatallevels of dopamine. Blood levels are presented as the mean ±SEM ngL-Dopa levels/ml blood. Striatal levels of dopamine are presented as themean ±SEM ng dopamine/ mg protein.

[0147] Blood and striatal levels of ¹⁴C following administration of¹⁴C-L-Dopa as generally described above were also determined and areshown in FIG. 3. A total of 25 μCi of radiolabeled L-Dopa was mixed withunlabelled L-Dopa to provide a total drug concentration of 8 mg/rat.Blood samples were taken at 2, 5 and 15 minutes post drug administrationL-Dopa (N=6 per time point for each group). At 5 or 15 minutes postL-Dopa, the striatum was removed and both the blood and tissues sampleswere assayed for ¹⁴C levels using scintillation. The zero minute plasmavalues are deduced from other many studies using radioactive agents.

[0148] Once again, a robust and rapid increase in plasma levels wasachieved via the pulmonary route, which was reflected in increaseddopamine activity in the brain at both the 5 minute and 15 minute timepoints (relative to oral administration).

[0149] Direct comparison of plasma ¹⁴C following administration of¹⁴C-L-Dopa via oral gavage, inhalation using a tracheotomy (as describedabove) or ventilator (Harvard Apparatus, Inc., Holliston, Mass.) isshown in FIG. 4. Corresponding brain ¹⁴C-L-Dogpa levels are shown inFIG. 5. All animals were briefly anesthetized using 1% Isoflurane andimmobilized in a harness to allow blood removal via a previously placedfemoral cannula. Blood samples were removed at 0, 2, 5, and 15 minutespost administration. For L-Dopa administration using the ventilator, a24 gauge catheter was placed within the trachea and the L-Dopa (25 μCi)was administered over a 3-5 second period using a tidal volume of 1 mland 100 strokes/minutes. Striatal tissue samples were processed fordeterminations of levels of radioactivity using scintillation counts.Both the plasma and brain levels of ¹⁴C were comparably elevated usingboth the conventional tracheotomy methods and the ventilator. Example 2

[0150] Blood, brain and peripheral organ levels of ¹⁴C were determinedfollowing administration of ¹⁴C- Carboplatin via either IV or pulmonaryadministration. A total of 100 μCi of radiolabeled carboplatin was mixedwith unlabelled carboplatin to provide a total drug concentration of 8mg/rat. All animals were anesthetized using ketamine. For IVadministration, carboplatin was administered via a previously placedfemoral cannula. For pulmonary administration, a 24 gauge catheter wasplaced within the trachea and the carboplatin was administered using aHarvard ventilator over a 3-5 second period using a tidal volume of 1 mland 100 strokes/minutes. Blood samples were taken at 10 minutes postdrug administration (N=6 per time point for each group). Brains wereremoved and dissected into various regions including the olfactory,frontal, and occipital cortices, the hippocampus, striatum, andcerebellum. Peripheral organs included the kidneys, spleen, heart,testes, and muscle. All samples were then processed for determinationsof ¹⁴C levels using scintillation.

[0151] Results are shown in Table 2, which shows scintillation counts of¹⁴C-levels in plasma, brain and peripheral organs following¹⁴C-carboplatin (100 μCi/8mg) administration, and in FIGS. 6A-6B and7A-7B. Absolute plasma levels of ¹⁴C were higher following IVadministration. However, the absolute brain levels were comparablesuggesting that delivery to the brain at this time point was relativelyselective. This point is clearer when the ratio of brain to blood ¹⁴Clevels was calculated. Following pulmonary delivery, ¹⁴C levels were2833% higher than observed following IV administration. Absolute levelsof ¹⁴C in peripheral tissue was also lower following pulmonaryadministration (92% lower relative to IV). In contrast to the largedifferences in selectivity seen in the brain, the relative peripheralselectivity (derived from dividing the levels of radioactivity inperipheral organs by that in the blood) was only 47% higher in thepulmonary group. Interestingly though, the highest levels of ¹⁴C inperipheral tissue were found in the heart. Together, these data suggestthat the brain and the heart may represent sites of preferentialdelivery at time point immediately following pulmonary drugadministration. TABLE 2 10 Minutes Plasma Levels IV 994.348 (n = 6) Lung102.215 (% Difference) −89.72% (n = 6) Absolute Brain Levels IV  29.47(nCi/gram) Lung  27.29 Relative Brain IV  0.03 Selectivity Lung  0.88(Brain/Blood) (% Difference) +2833% IV(Br/Bl)/Lung(Br/Bl) AbsoluteTissue IV  0.03 Levels Lung  0.88 (Peripheral Organs) (% Difference)+2833% *excludes kidney IV(Br/Bl)/Lung(Br/Bl) Relative Peripheral IV 0.44 Selectivity Lung  0.65 (Peripheral/Blood) (% Difference) +47.727%*excludes kidney IV(Per/Bl)/Lung(Per/Bl)

Example 3

[0152] Particles comprising L-Dopa and suitable for inhalation wereproduced as follows. 2.00123 g DPPC (Avanti Polar Lipids, Lot#G160PC-25)was added to 2.80 L of ethanol and stirred to dissolve. 0.0817 g L-Dopa(Spectrum, Lot 0Q0128, Laguna Hills, Calif.), 0.9135 g Sodium Citrate(Dehydrate) (Spectrum Lot NX0195), and 0.5283 g Calcium Chloride(Dehydrate) (Spectrum Lot NT0183) were added to 1.2 L of water anddissolved. The solutions were combined by adding the water solution tothe ethanol solution and then the solutions were allowed to stir untilthe solution was clear. The weight percent of the formulation wasapproximately: 20% L-Dopa, 50% DPPC, 20% Sodium Citrate, 10% CalciumChloride.

[0153] The final solution was then spray dried in a Niro dryer (Niro,Inc., Columbus, Md.) using a rotary atomizer and nitrogen drying gasfollowing the direction of the manufacturer, using the following sprayconditions: T_(inlet)=120° C., T_(outlet)=54° C., feed rate=65 ml/min,heat nitrogen=38 mm H₂O, atomizer speed=20,000 rpm (V24 atomizer used).

[0154] The resulting particle characteristics were: Mass MedianAerodynamic Diameter (MMAD)=2.141 μm and Volume Median GeometricDiameter (VMGD)=10.51 μm.

[0155] Under ketamine anesthesia, six rats received pulmonaryadministration of the formulation described above (20/50/20/10L-Dopa/DPPC/Sodium Citrate/Calcium Chloride).

[0156] The results are shown in FIG. 8. This FIG. shows blood levels ofL-Dopa following administration via oral gavage or direct administrationinto the lungs via insufflation. L-Dopa levels were measured using bothHPLC. Animals received an IP injection of the peripheral decarboxylaseinhibitor carbi-dopa (200 mg/kg) 1 hour prior to administration ofL-Dopa. Under ketamine anesthesia, the animals were divided into 2groups. In the first group, animals were fasted overnight and L-Dopa (8mg) was suspended in saline containing 1% methylcellulose and given viaoral gavage. In the second group, insufflation was used to deliver theL-Dopa formulation directly into the lungs. Blood samples (200 μl) werewithdrawn from a previously placed femoral cannula at the following timepoints: 0 (immediately prior to L-Dopa administration), 2, 5, 15, and 30minutes following L-Dopa administration. The increase in blood levels ofL-Dopa over time following oral administration was modest. In contrast,administration into the lungs produced a robust and rapid rise in L-Dopalevels. L-Dopa levels in this group remained elevated relative to oraldelivery at 30 minutes post drug administration. Data were normalized toa dose of 8 mg/kg (the total oral gavage dose). Data are presented asthe mean (±SEM) ng L-Dopa/ml blood.

Example 4

[0157] Ketoprofen/DPPC/maltodextrin particles were prepared andadministered in vivo.

[0158] Ketoprofen (99.5%) was obtained from Sigma, (St. Louis, Mo.),dipalmitoyl phosphatidyl choline (DPPC) from Avanti Polar Lipids,(Alabaster, Ala.) and maltodextrin,M100 (Grain Processing Corp.,Muscatine, Iowa).

[0159] To prepare ketoprofen/DPPC/Maltodextrin solutions, maltodextrin(0.598 g) was added to 0.60 L USP water. DPPC (0.901 g) was added to1.40 L ethanol and stirred until dissolved. The water and ethanolsolutions were combined, resulting in a cloudy solution. 500 ml of thisstock solution was used for each run. The addition of ketoprofen to theDPPC/Maltodextrin stock solution is described in Table 3.

[0160] A Niro Atomizer Portable Spray Dryer (Niro, Inc., Columbus, Md.)was used to produce the dry powders. Compressed air with variablepressure (1 to 5 bar) ran a rotary atomizer (2,000 to 30,000 rpm)located above the dryer. Liquid feed of the ketoprofen/DPPC/Maltodextrinsolutions, with varying rate (20 to 66 ml/min), was pumped continuouslyby an electronic metering pump (LMI, model#A151-192s) to the atomizer.Both the inlet and outlet temperatures were measured. The inlettemperature was controlled manually; it could be varied between 100° C.and 400° C., with a limit of control of 5° C. The outlet temperature wasdetermined by the inlet temperature and such factors as the gas andliquid feed rates; it varied between 50° C. and 130° C. A container wastightly attached to the 6Δ cyclone for collecting the powder product.The spraying conditions for each solution is given in Table 4, whichshows that the spraying conditions were held nearly constant throughoutthe study. The total recovery and yield for each solution is given inTable 5.

[0161] The particles were characterized using the Aerosizer (TSI, Inc.,Amherst, Mass.) and the RODOS dry powder disperser (Sympatec Inc.,Princeton, N.J.) as instructed by the manufacturer. For the RODOS, thegeometric diameter was measured at 2 bars. The material from run#5 wasalso characterized using a gravimetric collapsed Andersen CascadeImpactor (ACI, 2 stage, Anderson Inst., Sunyra, Ga.). The samples wereexamined using a scanning electron microscope (SEM).

[0162] Table 5 indicates that increasing the weight % of ketoprofen ledto a decrease in yield. The addition of ketoprofen to the stock solutionlinearly decreased yield. This may be due to a decrease in meltingtemperature for DPPC when mixed with ketoprofen, leading to the yieldloss.

[0163] Table 6 shows that the particles ranged in diameter from 8.8 μmto 10.2 μm (VMGD) and from 2.65 μm to 3.11 μm (MMAD). The lowest MMADparticles were for the 8.4% loading material (run#5).

[0164] Table 7 shows the results of a Andersen Collapsed Impactor study(ACI, gravimetric, n=2) of the material from run#5, the 8.4% loadingmaterial. The fine particle fractions (FPF) below 5.6 μm and below 3.4μm are consistent with powders expected to be respirable. TABLE 3 SampleID Ketoprofen added (mg) Total solids (g/L) % Ketoprofen Run #1 0 1.0000 Run #2 8.0 1.016 1.6 Run #3 15.1 1.030 3.0 Run #4 30.1 1.060 5.7 Run#5 46.0 1.092 8.4 Run #6 63.0 1.126 11.2

[0165] TABLE 4 Sam- Temperature Liquid Gas Rotor ple (° C.) FeedPressure Speed Inlet Dew- ID Inlet Outlet (ml/min) (mmH₂O) (RPM) point(° C.) Run #1 115 36 75 40 18,600 −27.0 Run #2 113 38 85 40 18,400 −26.8Run #3 110 38 85 39 18,300 −26.4 Run #4 110 39 85 38 18,400 −25.9 Run #5110 38 86 39 18,400 −25.4 Run #6 110 38 85 38 18,400 −25.0

[0166] TABLE 5 Weight Theoretical Actual Yield Sample ID Collected (mg)Yield (mg) (% Theoretical) Run #1 186 500 37.2 Run #2 195 508 38.4 Run#3 147 515 28.5 Run #4 127 530 24.0 Run #5 89 546 16.3 Run #6 67 56311.9

[0167] TABLE 6 MMAD MGVD Sample ID (μm) Std Dev (μm, 2 bar) Run #1 3.111.48 9.0 Run #2 3.01 1.37 9.3 Run #3 2.83 1.40 10.3 Run #4 2.84 1.4110.4 Run #5 2.65 1.39 9.8 Run #6 2.83 1.38 8.8

[0168] TABLE 7 Stage 0  1.33 mg Stage 2  2.75 mg Stage F  3.17 mgCapsule Fill 12.37 mg Weight <5.6 μm 5.92 FPF_(5.6) 0.479 Weight <3.4 μm3.17 FPF_(3.4) 0.256

[0169] 350 mg of particles containing 8% ketoprofen in 60/40DPPC/maltodextrin were produced as described above and administered to20 Sprague Dawley rats. Each of 8 rats were given 7 mg of powder viainsufflation, and each of 7 rats were orally given 7 mg of powderdissolved in 50% ethanol. Time points were set at 0, 5, 15 , 30, 60,120, 240, 360 and 480 minutes. For t=0, 4 animals were tested withoutdosing. For each time point after, samples were taken from either 3 or 4rats. Each rat was used for 4 time points, with 3 or 4 animals each infour groups. The animals were distributed as follows: 3 animals oral at5, 30, 120, 360 minutes; 4 animals insufflation at 15, 60, 240, 480minutes. Sufficient blood was drawn at each time point for theketoprofen plasma assay. Blood samples were centrifuged, the plasmacollected and then frozen at −20° C. prior to shipment to the contractlaboratory for analysis. The assay used in this study has a lowerdetection limit of 1.0 mg/ml.

[0170] Rats were dosed with ketoprofen via either oral or pulmonaryadministration to determine if the pulmonary route would alter the timerequired to achieve maximum plasma concentration. The results (FIGS.9-11) show that the pulmonary delivery route leads to a very rapiduptake with C_(max) occurring at <10 minutes. The rats that receivedoral doses of ketoprofen displayed somewhat anomalous pharmacokineticbehavior, with the relative bioavailability being about half of thatdisplayed for rats dosed via the pulmonary route. This result wasunexpected as ketoprofen is 90% orally bioavailable in the human model.This anomaly for the orally dosed rats does not, however, invalidate thesignificance of the early C_(max) seen for the rats dosed via thepulmonary route.

[0171] The results are provided in Table 8. The averages were calculatedalong with the standard errors and p values. The results are alsopresented graphically in FIGS. 9-11, wherein FIG. 9 shows both datasets, FIG. 10 gives the oral dosing results and FIG. 11 shows theinsufflation results. For FIG. 9, points with p°0.05 are marked with “*”and points with p°0.01 are marked with “**” For FIGS. 10 and 11, AUC(area under the curve) was performed via numerical integration of thecurve with smooth interpolation.

[0172] At t=0, all rats showed ketoprofen levels below the detectionlimit for the assay. From t=5min to t=60 min, the insufflated rats hadsignificantly higher plasma levels of ketoprofen. At t=120 min and t=240min, the plasma levels of ketoprofen of the two groups werestatistically equivalent. At t=360 min and t=480, the plasma levels ofketoprofen for both groups approached the detection limit for the assay.

[0173] The ratio of the AUCs for insulflated rats vs. orally dosed wasabout 2. The plasma concentrations for ketoprofen at the early timepoints were statistically significant as well.

[0174] C_(max) for the insufflated rats clearly occurred at <15 min andC_(max) for the orally dosed rats occurred between 15-60 min. Due to thelarge standard error and the relatively low plasma levels for thisgroup, it is not possible to accurately determine the time required forCmax.

[0175] Pulmonary administration resulted in Cmax occurring very quickly(<15 min) to oral dosing (t=15 to 60 min).

[0176] The insufflated rats showed higher bioavailability compared tothe orally dosed rats. This unexpected as previous studies have shownketoprofen to have consistently high (°90%) bioavailability in humanswhen dosed orally, subcutaneously or rectally. Since the pharmokineticbehavior of ketoprofen delivered orally is well-known, the anomalousresults seen here for the orally dosed group do not invalidate theresults seen for the insufflation group. TABLE 8 Time Oral Dosing GroupPulmonary Dosing Group Min. Avg. (ug/ml) St. Dev. Avg. (ug/ml) Std. Dev.P Value 0 1.0 N/A 1.0 N/A 5 1.7 0.75 9.6 1.27 0.0003 15 2.1 0.76 7.60.28 0.0000 30 1.9 0.12 5.5 0.76 0.0012 60 2.0 0.13 4.5 0.60 0.0002 1201.7 0.31 2.4 0.44 0.0929 240 1.4 0.05 1.8 0.63 0.2554 360 1.0 0.06 1.80.35 0.0224 480 1.0 0.00 1.3 0.47 0.2174

Example 5

[0177] The following experimental methods and instrumentation wereemployed to determine the physical characteristics of particlesincluding L-DOPA and suitable for pulmonary delivery.

[0178] Aerodynamic diameter was analyzed using the API AeroDisperser andAerosizer (TSI, Inc., St. Paul, Minn.) following standard procedures(Alkermes SOP# MS-034-005). Sample powder was introduced and dispersedin the AeroDisperser and then accelerated through a nozzle in theAerosizer. A direct time-of-flight measurement was made for eachparticle in the Aerosizer, which was dependent on the particle'sinertia. The time-of-flight distribution was then translated into amass-based aerodynamic particle size distribution using a force balancebased on Stokes law.

[0179] Geometric diameter was determined using a laser diffractiontechnique (Alkermes SOP# MS-021-005). The equipment consists of a HELOSdiffractometer and a RODOS disperser (Sympatec, Inc., Princeton, N.J.).The RODOS disperser applies a shear force to a sample of particles,controlled by the regulator pressure of the incoming compressed air. Thedispersed particles travel through a laser beam where the resultingdiffracted light pattern produced is collected by a series of detectors.The ensemble diffraction pattern is then translated into a volume-basedparticle size distribution using the Fraunhofer diffraction model, onthe basis that smaller particles diffract light at larger angles.

[0180] The aerodynamic properties of the powders dispersed from theinhaler device were assessed with a 2-stage MkII Anderson CascadeImpactor (Anderson Instruments, Inc., Smyrna, Ga.). The instrumentconsists of two stages that separate aerosol particles based onaerodynamic diameter. At each stage, the aerosol stream passes through aset of nozzles and impinges on the corresponding impaction plate.Particles having small enough inertia will continue with the aerosolstream to the next stage, while the remaining particles will impact uponthe plate. At each successive stage, the aerosol passes through nozzlesat a higher velocity and aerodynamically smaller particles are collectedon the plate. After the aerosol passes through the final stage, a filtercollects the smallest particles that remain.

[0181] Prior to determining the loading of drug within a dry powder, thedrug had to be first be separated from the excipients within the powder.An extraction technique to separate L-Dopa from the excipient DPPC wasdeveloped. Particles were first dissolved in 50% chloroform/50%methanol. The insoluble L-Dopa was pelleted out and washed with the samesolvent system and then solubilized in 0.5 M hydrochloric acid. DPPC wasspiked with L-DOPA to determine recovery. Samples were injected onto areverse phase high pressure liquid chromatography (HPLC) for analysis.

[0182] Separation was achieved using a Waters Symmetry C18 5 μm column(150-mm×4.6-mm ID). The column was kept at 30° C. and samples were keptat 25° C. Injection volume was 10 μL. The mobile phase was prepared from2.5% methanol and 97.5% aqueous solution (10.5 g/L citric acid, 20 mg/LEDTA, 20 mg/L 1-octanesulfonic acid sodium salt monohydrate). Mobilephase was continually stirred on a stir plate and degassed through aWaters in-line degassing system. L-Dopa was eluted under isocraticconditions. Detection was performed using an ultraviolet detector set atwavelength 254 nm.

[0183] Since the average single oral dose of L-Dopa generally rangesfrom 100-150 mg, experiments were conducted to prepare particlessuitable for inhalation which included high loads of L-Dopa.Formulations of 20% and 40% L-Dopa load were studied. Carbidopa, adecarboxylase inhibitor given in conjunction with L-Dopa to preventperipheral decarboxylation, was also included at a 4:1 weight/weight(w/w) ratio in some of the formulations. L-Dopa and combination ofL-Dopa and carbidopa were successfully sprayed with DPPC formulations.The optimal formulation consisted of L-Dopa and/or carbidopa, 20% (w/w)sodium citrate, and 10% (w/w) calcium chloride, and the remainderdipalmitoyl phosphatidyl chloline (DPPC).

[0184] Details on formulations and the physical properties of theparticles obtained are summarized in Table 9. The aerodynamic size orthe mass median aerodynamic diameter (MMAD) was measured with anAerosizer, and the geometric size or the volume median geometricdiameter (VMGD) was determined by laser diffraction, and the fineparticle fraction (FPF) was measured using a 2-stage Andersen CascadeImpactor. As shown in FIG. 12 and by the VMGD ratios in Table 9, thepowders were flow rate independent. Scanning electron micrography wasemployed to observe the particles. TABLE 9 Load (%) VMGD ID ratio L-VMGD (μm) 0.5/4.0 MMAD FPF(%) Dopa/Carbidopa Yield(%) at 2 bar bar (μm)5.6/3.4 20/0  >40 9.9 NA 2.7 NA 40/0  >40 8.0 1.2 3.3 42/17 20/5    4210 1.6 3.1 64/38 40/10 >20 7.4 1.6 3.8 40/14

[0185] L-Dopa integrity appeared to be preserved through the formulationand spray drying process. L-Dopa was extracted from L-Dopa powders andanalyzed by reverse phase HPLC. No impurities were detected in theL-Dopa powders (FIG. 13A); the early peaks eluted around 1-2 minutes aredue to solvent as can be seen from FIG. 13B which is a blank sample thatdid not contain L-Dopa. The purity of L-Dopa recovered from theparticles was 99.8% and 99.9% respectively for the 20% and 40% loadedparticles.

[0186] To determine the loading (weight percent) of L-Dopa within thepowder, the L-Dopa was first separated from the excipients in theformulation and then analyzed by reverse phase HPLC. Results of theL-Dopa recovery from the powders and the final load calculations aregiven in Table 10. Both extraction recoveries and load determinationwere satisfactory. The determined actual weight percent of L-Dopa in thepowder was approximately 87% of the theoretical drug load. TABLE 10Powder Extraction Formulation recovery % Actual load (%) 20/0 100 ± 4.517.3 ± 0.2 40/0 101 ± 2.8 35.0 ± 5.4

Example 6

[0187] Determinations of plasma levels of L-Dopa were made following IVinjection, oral gavage, or insufflation into the lungs. Carbidopagenerally is administered to ensure that peripheral decarboxylaseactivity is completely shut down. In this example, animals received anintraperitoneal (IP) injection of the peripheral decarboxylase inhibitorcarbidopa (200 mg/kg) 1 hour prior to administration of L-Dopa. Underketamine anesthesia, the animals were divided into 3 groups. In thefirst group of animals, L-Dopa (2 mg) was suspended in saline containing1% methylcellulose and 1% ascorbic acid and given via oral gavage. Inthe second group, an insufflation technique was used for pulmonaryadministration of particles including L-Dopa (20% loading density). Alaryngoscope was used to visualize the rat's epiglottis and theblunt-tip insufflation device (PennCentury Insufflation powder deliverydevice) was inserted into the airway. A bolus of air (3 cc), from anattached syringe, was used to delivery the pre-loaded powder from thechamber of the device into the animal's lungs. A total of 10 mg ofpowder (2 mg L-Dopa) was delivered. In the third group, apreviously-placed femoral cannula was used to delivery a bolus (2-3second) of L-Dopa (2 mg). Blood samples (200 μL) were withdrawn fromeach animal using the femoral cannula at the following timepoints: 0(immediately prior to L-Dopa administration), 2, 5, 15, 30, 60, 120, and240 minutes following L-Dopa administration. All samples were processedfor L-Dopa determinations using HPLC.

[0188] The results of a pharmacokinetic study using the proceduredescribed are shown in FIGS. 14A and 14B. The results of a comparison ofpulmonary delivery of L-Dopa with oral administration are depicted inFIG. 14A. Following insufflation, peak plasma levels of L-Dopa were seenat the earliest time point measured (2 minutes) and began to decreasewithin 15 minutes of administration while still remaining elevated,relative to oral administration, for up to 120 minutes. In contrast,oral administration of L-Dopa resulted in a more gradual increase inplasma L-Dopa levels, which peaked at 15-30 minutes followingadministration and then decreased gradually over the next 1-2 hours.

[0189] Intravenous, oral and pulmonary delivery also were compared. Theresults are shown in FIG. 14B. This panel depicts the same datapresented in FIG. 14A with the addition of the IV administration groupwhich allows direct comparisons of the plasma L-Dopa levels obtainedfollowing all three routes of administration (pulmonary, oral, and IV).Data are presented as the mean ±SEM μg L-Dopa/mL blood. Plasma levels ofL-Dopa rapidly increased following intravenous (IV) administration. Thehighest levels of L-Dopa were seen at 2 minutes and decreased rapidlythereafter. Bioavailability was estimated by performing area under thecurve (AUC) calculations. Over the entire time course of the study(0-240 min), the relative bioavailability (compared to IV) of pulmonaryL-Dopa was approximately 75% as compared 33% for oral L-Dopa. Therelative bioavailability of pulmonary L-Dopa at 15 min and 60 min postadministration was 38% and 62%, respectively, while that of oral L-Dopawas 9% and 24%, respectively.

Example 7

[0190] Pharmacodynamic evaluation of rats receiving L-Dopa also wasundertaken. Rats received unilateral injections of the neurotoxin 6-OHDA(specific for dopamine neurons in the brain) into the medial forebrainbundle. Rats were then screened to assure successful striatal dopaminedepletion using a standard apomorphine-induced turning paradigm.Beginning two weeks after surgery, animals were tested weekly for threeweeks for apomorphine-induced rotation behavior. For this test, animalsreceived an IP injection of apomorphine (0.25 mg/kg for the first testand 0.1 mg/kg for the following two tests) and were placed into acylindrical Plexiglass bucket. Each 360-degree rotation was counted for30 minutes and only those animals exhibiting >200 rotations/30 minutes(12/30 lesioned rats) were used in behavioral testing.

[0191] The lesioned rats were challenged with several motor tasks postL-Dopa administration. The data from the studies (placing task, bracingtask, akinesia) further emphasized the advantage of pulmonary deliveryover oral delivery.

[0192] In one test, animals passing the apomorphine challenge weretested using a “placing task”. Prior to each test day, animals receivedan IP injection of the peripheral decarboxylase inhibitor carbidopa (200mg/kg). Animals then received oral L-Dopa (0, 20 or 30 mg/kg) orpulmonary L-Dopa (0, 0.5, 1.0 or 2.0 mg of L-Dopa) and were tested 15,30 60 and 120 minutes later. Throughout testing with oral and pulmonarydelivery of L-Dopa, each animal received every possible drug combinationin a randomized fashion.

[0193] The pharmacodynamics “placing task” required the animals to makea directed forelimb movement in response to sensory stimuli. Rats wereheld so that their limbs were hanging unsupported. They were then raisedto the side of a table so that their bodies were parallel to the edge ofthe table. Each rat received 10 consecutive trials with each forelimband the total number of times the rat placed its forelimb on the top ofthe table was recorded. Results from a “placing task” tests are shown inFIGS. 15A and 15B. At baseline (t=0; immediately prior to L-Dopaadministration), the animals performed nearly perfectly on this taskwith the unaffected limb, making greater than 9/10 correct responses. Incontrast, the animals were markedly impaired in their ability to performthe same task with the impaired limb, making approximately 1 correctresponse over the 10 trials.

[0194] Oral L-Dopa (FIG. 15A) produced a dose-related improvement inperformance with the impaired limb. At the highest dose tested (30mg/kg), performance was improved, relative to saline control, within 30minutes and peaked between 1-2 hours after drug administration. Thelower dose (20 mg/kg) also improved performance slightly with maximaleffects at 60 minutes and stable performance thereafter. No changes werenoted following administration of the saline control.

[0195] In contrast to oral administration, performance on the “placingtask” rapidly improved following pulmonary delivery of L-Dopa, as seenin FIG. 15B. At the highest dose tested, significant improvementsoccurred within 10 minutes, with peak benefits observed within 15-30minutes (as opposed to 1-2 hours with oral administration). Theseeffects were dose-related, with significant improvements seen with dosesas low as 0.5 mg of L-Dopa. In comparison to the recovery shown withoral delivery, the behavioral improvements were seen with markedly lowertotal doses using the pulmonary route. For instance, the extent ofrecovery with 30 mg/kg of L-Dopa given orally was comparable to therecovery seen with 1 mg of L-Dopa given by the pulmonary route (notethat 1 mg of pulmonary L-Dopa is equivalent to approximately 3 mg/kg,given that the animals body weight was approximately 300 g).Accordingly, when the L-Dopa doses were normalized by body weight, thisrepresented nearly a 10-fold difference in the drug required to produceequivalent efficacy. Finally, the persistence of the behavioralimprovements was comparable using the two delivery routes.

[0196] Results from a bracing test are shown in FIGS. 16A and 16B. Thistest was performed using the same animals and at the same time as the“placing task” test described above. Rats were placed on a smoothstainless steel surface and gently pushed laterally 90 cm atapproximately 20 cm/second. The number of steps the rat took with theforelimb on the side in which the rat was moving was recorded. Eachtrial included moving the rat 2 times in each direction.

[0197] The animals demonstrated a profound impairment in their abilityto perform this task with the impaired limb, making approximately 3responses compared to approximately 7 with the unaffected limb, as seenin FIG. 16A. Again, oral administration improved performance on thistask in a dose-related manner. Administration of 30 mg/kg (approximately10 mg L-Dopa) improved performance within 30 minutes. Maximal effectswere seen within 60 minutes and remained stable thereafter. A lower doseof oral L-Dopa (20 mg/kg or approximately 7 mg of L-Dopa) slightlyimproved performance. Again, administration of the saline control didnot affect performance.

[0198] In contrast to oral administration, performance on this taskrapidly improved following pulmonary administration of L-Dopa, as shownin FIG. 16B. Significant improvements were seen within 10 minutes, withpeak benefits observed within 15-30 minutes (as opposed to 30-60 minuteswith oral administration). These effects were dose-related, with modest,but statistically significant improvements seen with as low as 0.5 mg(equivalent to approximately 1.5 mg/kg). As with the other functionaltests, the behavioral improvement achieved following pulmonary L-Dopaoccurs at doses far below those required to achieve a similar magnitudeof effect following oral delivery. Finally, the persistence of thebehavioral improvements was comparable using the two delivery routes.

[0199] A functional akinesia pharmacodynamics study also was conducted.The results are shown in FIGS. 17A and 17B. This test was performedusing the same animals and at the same time as the two preceding tests.In this task, the animal was held so that it was standing on oneforelimb and allowed to move on its own. The number of steps taken withthe forelimb the rat was standing on was recorded during a 30 secondtrial for each forelimb.

[0200] As was seen with the placing and bracing tests, the animalsdemonstrated a profound impairment in their ability to perform theakinesia task with the impaired limb. While the animals madeapproximately 17 steps with the normal limb, they made fewer than halfthis number with the impaired limb (range=0-10 steps). Oraladministration (FIG. 17A) improved performance on this task in adose-related manner. Administration of 30 mg/kg (approximately 10 mgL-Dopa) improved performance within 30 minutes and maximal effects wereseen within 60 minutes. A lower dose of oral L-Dopa (20 mg/kg orapproximately 6.8 mg of L-Dopa) produced the same pattern of recoveryalthough the absolute magnitude of improvement was slightly lower thanthat seen with the higher dose of L-Dopa. Performance remained stablebetween 60 and 120 minutes following administration of both doses.Administration of the saline control did not affect performance.

[0201] In contrast to oral administration, performance on this taskrapidly improved following pulmonary administration of L-Dopa, asdepicted in FIG. 17B. Significant improvements were seen within 10minutes, with peak benefits observed within 15-30 minutes (as opposed to60 minutes with oral administration). These effects were dose-relatedstatistically significant (p<0.05) improvements seen with as low as 1.0mg. As with the other functional tests, the behavioral improvementachieved following pulmonary L-Dopa occurred at doses far below thoserequired to achieve a similar magnitude of effect following oraldelivery. Finally, the persistence of the behavioral improvements wascomparable using the two delivery routes.

[0202] Animals also were tested on a standard pharmacodynamics rotationtest known to be a sensitive and reliable measure of dopamine activityin the brain. For this test, animals received either oral L-Dopa (30mg/kg or approximately 10 mg total) or pulmonary L-Dopa (2 mg total).These doses were chosen for this test because they represent the dosesof L-Dopa shown to produce maximal efficacy in the previous functionaltests. Following dosing, animals were placed into a cylindricalPlexiglas bucket. Each 360-degree rotation was counted and grouped into5 minute bins over a 120 minute test period. Animals were also testedfor rotation behavior with and without pre-treatment with carbidopa.

[0203] All of the animals used in these studies received unilateralinjections of 6-OHDA. Because the dopamine depletions are unilateral,the uninjected side remained intact and still able respond to changes indopamine activity. When these animals were injected with a dopamineagonist (i.e. L-Dopa) brain dopamine activity was stimulatedpreferentially on the intact side. This resulted in an asymmetricalstimulation of motor activity that was manifested as a turning orrotational behavior. The onset and number of rotations provided ameasure of both the time course as well as the extent of increaseddopamine activity.

[0204] The results are shown in FIG. 18. Oral administration of L-Dopaproduced a marked clockwise rotation behavior that was modest during thefirst 10-15 minutes post L-Dopa administration (<5 rotations/animal).During the next 20 minutes, the number of rotations increased markedly,with peak levels occurring approximately 30 minutes after L-Dopaindicating increased dopamine activity in the intact striatum of thebrain. During the next 90 minutes, the number of rotations graduallydecreased, but this decrease, relative to peak levels, did not reachstatistical significance (p>0.05).

[0205] In contrast to oral administration, pulmonary delivery of L-Doparapidly increased rotation behavior indicating much more rapidconversion of L-Dopa to dopamine in the intact striatum. Rotations inthis group were greater than 3 times that produced by oral deliverywithin the first 10-15 minutes. The numbers of rotations increasedslightly, peaked at 25-30 minutes, and remained relatively stablethereafter. While a trend towards increased rotations, relative to oraldelivery, was seen 120 minutes after dosing, this did not reachstatistical significance (p >0.05). Rotation behavior was virtuallyeliminated in animals that did not receive pre-treatment with carbidopa(data not shown).

Example 8

[0206] The pharmacodynamic effects of a pulmonary versus oralbenzodiazepine-type drug, alprazolam, were evaluated using a standardpre-clinical test of anxiolytic drug action. In this test, the chemicalconvulsant pentylenetetrazol (PZT), which is known to produce wellcharacterized seizures in rodents, was administered to rats. The testwas selected based on its sensitivity to a wide range of benzodiazapinesand to the fact that the relative potency of benzodiazapines in blockingPZT-induced seizures is believed to be similar to the magnitude of theiranti-anxiety effects in humans. The ability of alprazolam to blockPZT-induced seizures was used as a measure of the pharmacodynamiceffects of alprazolm.

[0207] Determinations of the anti-anxiolytic activity of alprazolam weremade following oral gavage, or insufflation directly into the lungs ofrats. Alprazolam (Sigma, St. Louis, Mo. was administered viaaerodynamically light particles which included 10% alprazolam, 20%sodium citrate, 10% calcium chloride and 60% DPPC. For oral delivery,alprazolam was suspended in light corn syrup and administered viagavage. For pulmonary delivery, an insufflation technique was used.Animals were briefly anesthetized with isoflurane (1-2%) and alaryngoscope was used to visualize the epiglottis and the blunt-tipinsufflation device (PennCentury Insufflation powder delivery device)was inserted into the airway. A bolus of air (3 cc), from an attachedsyringe, was used to deliver the pre-loaded powder from the chamber ofthe device into the animals' lungs. The doses for pulmonary deliverywere 0 (blank particles that included 20% sodium citrate, 10% calciumchloride and 70% DPPC), 0.088, 0.175, or 0.35 mgs total alprazolam, andthe doses for oral delivery were 0, 0.088, 0.175, 0.35, 0.70, 1.75, or3.50 mgs total alprazolam. These doses were chosen to encompass therange of effective and ineffective oral doses. Accordingly, anypotential benefits of pulmonary delivery could be directly compared tothe oral dose response curve for alprazolam.

[0208] For both oral and pulmonary delivery, alprazolam was administeredeither 10 or 30 minutes prior to PZT, obtained from Sigma, St. Louis,MO, (60 mg/kg given i.p). To control for potential interactions betweenalprazolam and isoflurane, all animals receiving oral alprazolam alsoreceived isoflurane immediately following dosing as described above. Forall animals, the number of seizures as well as the time to seizure onsetand seizure duration was recorded for 45 minutes after administration ofPZT. Any animal that did not exhibit seizure activity was assigned themaximum possible time for seizure onset (45 minutes) and the minimalpossible time for seizure duration (0 seconds).

[0209] Pulmonary delivery of alprazolam produced a rapid and robustdecrease in the incidence of seizures, as shown in Table 11. While 80%of control animals (blank particles) exhibited seizures, pulmonaryalprazolam produced a robust and dose-related decrease in the number ofanimals manifesting seizures when administered 10 minutes prior to PZT.With alprazolam doses as low as 0.088 mgs, only 33% of the animals hadseizures. With further dose escalation to 0.35 mgs of alprazolam,seizure activity was virtually eliminated with only 13% of the animalsexhibiting seizures.

[0210] In contrast to the rapid and robust effects of pulmonaryalprazolam, the effects of oral delivery were delayed (Table 11). Whengiven 30 minutes prior to PZT, oral alprazolam produced a dose-relateddecrease in seizures. While only 27% of the animals had seizuresfollowing the highest dose tested (0.35 mgs), this same dose ofalprazolam was ineffective when administered only 10 minutes prior toPZT (i.e, a dose that was maximally effective when administered by thepulmonary route). These studies also demonstrated that when given 10minutes prior to PZT, approximately 10 times the oral dose of alprazolamwas required to achieve seizure suppression comparable to pulmonarydelivery. While only 13% of the animals that received 0.35 mgs ofparticles including alprazolam had seizures, the oral dose required toproduce this effect was 3.50 mgs.

[0211] The benefits of pulmonary delivery over oral delivery were alsoevident when examining the time to seizure onset (Table 11 and FIG.19A). The effects of oral alprazolam were again delayed relative topulmonary administration. As shown above, oral delivery was markedlyless effective when alprazolam was given 10 minutes versus 30 minutesbefore PZT. In contrast, all doses of pulmonary alprazolam producedrapid and robust effects when given only 10 minutes prior to PZT. Notonly were the effects of pulmonary delivery more rapid, but theeffective pulmonary dose was markedly lower than the effective oraldose. For instance, when comparable doses of alprazolam (0.35 mgs) wereadministered by both the oral and pulmonary routes 10 minutes prior toPZT, pulmonary administration resulted in seizure onset times that werenearly maximal (>42 minutes). Oral administration of the same dose ofalprazolam, however, did not increase the latency to seizure onsetrelative to control animals. In fact, oral alprazolam did notsignificantly increase the time to seizure onset until the dose wasescalated to 1.75 mgs and effects comparable to those obtained withpulmonary delivery required an oral dose that was 10 times higher thanthe pulmonary dose (0.35 vs 3.50 mgs).

[0212] Similar results were also observed when quantifying the effectsof the route of alprazolam administration on the duration of the seizure(Table 11 and FIG. 19B). Pulmonary administration exerted a more rapideffect and also required substantially less total drug relative to oralalprazolam. Again, oral delivery was markedly less effective at reducingthe duration of seizures when alprazolam was given 10 minutes versus 30minutes before PZT. Moreover, the maximally effective oral dose,delivered 10 minutes prior to PZT, was 3.50 mgs of alprazolam. Incontrast, pulmonary delivery of only 0.088 mgs of alprazolam (nearly40-fold lower than the maximally effective oral dose) produced acomparable decrease in seizure duration.

[0213] A time course analysis revealed that while the relativeadvantages of pulmonary over oral alprazolam declined as the intervalbetween alprazolam and PZT was increased, pulmonary delivery remained aseffective as oral delivery. While oral alprazolam became increasinglymore effective as the interval between alprazolam and PZT treatmentincreased from 10 to30 minutes, the effects of pulmonary deliveryremained relatively constant over the same time period. In fact, nodifferences in seizure activity were seen when comparable oral andpulmonary doses of alprazolam were delivered 30 minutes prior to PZT.While a trend towards fewer seizures was seen with pulmonary delivery,these differences were modest and did not reach statistical significance(Table 11B; p>0.05). Moreover, no statistically significant differenceswere observed between any oral and pulmonary dose when comparing thetime to seizure onset or the duration of those seizures (FIG. 20A and11B).

[0214]FIG. 21A and 21B further demonstrate that the effects of pulmonaryalprazolam remained relatively constant as the time between alprazolamand PZT treatment increased. Importantly though, a detailed analysis ofthe results indicated that alprazolam was modestly more effective whenthe interval between alprazolam and PZT was kept at a minimum. At eachdose tested, fewer animals had seizures when alprazolam was delivered 10minutes vs 30 minutes prior to PZT (although this effect did not reachstatistical significance, p>0.05). The benefit of maintaining a closetemporal relationship between alprazolam and PZT was also beginning toemerge when examining the time to seizure onset and the duration ofseizure activity. While no differences were seen at the higheralprazolam doses (0.175 and 0.35 mgs), animals receiving the lowest doseof alprazolam (0.088 mgs) 10 minutes prior to PZT showed significantlyincreased times for seizure onset and significantly decreased seizuredurations relative to animals treated 30 minutes prior to PZT (FIG. 3).TABLE 11 Effects of Alprazolam on PZT-Induced Seizures Minutes toDuration of Animals With Seizure Seizure Route Seizures Onset (seconds)Pulmonary   10 minutes prior to PZT Blank 12/15 (80%) 11.72 (4.63)  83.0(26.04) 0.088 mgs  5/15 (33%) 36.71 (3.93)   7.0 (3.53) 0.175 mgs  3/15(20%) 38.61 (3.81)   8.0 (4.3)  0.35 mgs  2/15 (13%) 42.28 (1.98)   4.0(2.60)   30 minutes prior to PZT Blank 15/15 (100%)  9.58 (2.25) 120.13(49.33) 0.088 mgs  9/15 (60%) 18.47 (5.50)  82.67 (33.0) 0.175 mgs  5/15(33%) 34.05 (4.20)  16.07 (6.89)  0.35 mgs  2/15 (13%) 41.98 (2.18) 2.69 (1.90) Oral   10 minutes prior to PZT  0.35 mgs 13/15 (87%) 11.49(3.80)  88.0 (49.22)  0.70 mgs 13/15 (87%)  9.24 (3.93)  62.07 (14.58) 1.75 mgs  7/15 (47%) 29.03 (4.41)  14.47 (4.04)  3.50 mgs  2/14 (14%)43.37 (1.52)  5.40 (3.47)   30 minutes prior to PZT    0 mgs 13/15 (87%) 8.75 (3.95)  96.0 (26.08) 0.088 mgs 11/15 (73%) 18.38 (4.55)  46.0(14.48) 0.175 mgs  7/15 (47%) 33.10 (4.07)  15.0 (6.75)  0.35 mgs  4/15(27%) 37.58 (3.50)  19.0 (12.36)

[0215] While this invention has been particularly shown and describedwith references to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form and details maybe made therein without departing from the scope of the inventionencompassed by the appended claims.

1-16. canceled.
 17. A method for treating a disorder of the centralnervous system comprising administering to the respiratory tract of apatient in need of treatment a drug for treating said disorder, whereinthe drug is administered in a dose that is at least about two times lessthan that required by oral administration and wherein delivery is to thepulmonary system.
 18. The method of claim 17 wherein the dose is betweenabout two times and about five times less than that required by oraladministration.
 19. The method of claim 17 wherein the dose is betweenabout two times and about ten times less than that required by oraladministration.
 20. The method of claim 17 wherein delivery is to thealveoli region of the pulmonary system.
 21. The method of claim 17wherein administering is for rescue therapy.
 22. The method of claim 17wherein administering is during ongoing treatment.
 23. The method ofclaim 17 wherein the disorder is Parkinson's disease.
 24. The method ofclaim 17 wherein the patient in need of treatment is suffering fromdiseases selected from the group consisting of migraine, anxiety,psychosis, depression, bipolar disorder, obsessive compulsive disorder,convulsions, seizures, epilepsy, Alzheimer's, attention deficithyperactivity disorder and migraines.
 25. The method of claim 17 whereinthe drug is present in dry powder particles.
 26. The method of claim 25wherein the drug is present in the dry powder particles in an amount ofat least 20 weight percent.
 27. The method of claim 25 wherein the drugis present in the dry powder particles in an amount of at least 40weight percent.
 28. The method of claim 25 wherein the drug is presentin the dry powder particles in an amount of at least 50 weight percent.29. The method of claim 25 wherein the particles have a tap density ofless than about 0.4 g/cm³.
 30. The method of claim 25 wherein theparticles have a mass median aerodynamic diameter of less than about 5microns.
 31. The method of claim 25 wherein the particles have a massmedian geometric diameter greater than about 5 microns.
 32. The methodof claim 25 wherein the particles have a mass median aerodynamicdiameter of less than about 3 microns.
 33. The method of claim 25wherein the particles include a phospholipid.
 34. The method of claim 25wherein the particles include citrate and a multivalent salt.
 35. Themethod of claim 25 wherein the particles include an amino acid.
 36. Themethod of claim 35 wherein the amino acid is leucine.
 37. The method ofclaim 25 wherein the particles are administered via a dry powderinhaler.
 38. The method of claim 17 further comprising co-administeringat least one additional agent.
 39. A method for treating Parkinson'sdisease comprising administering to the respiratory tract of a patientin need of treatment or rescue therapy a drug for treating Parkinson'sdisease wherein the drug is administered in a dose that is at leastabout two times less than that required by oral administration andwherein delivery is to the pulmonary system.
 40. The method of claim 39wherein the drug is levodopa.
 41. The method of claim 39 wherein thedose is between about two times and about five times less than thatrequired by oral administration.
 42. The method of claim 39 wherein thedose is between about two times and about ten times less than thatrequired by oral administration.
 43. The method of claim 39 whereindelivery is to the alveoli region of the pulmonary system.
 44. Themethod of claim 39 wherein administering is for rescue therapy.
 45. Themethod of claim 39 wherein administering is during ongoing treatment.46. The method of claim 39 wherein the drug is present in dry powderparticles.
 47. The method of claim 46 wherein the drug is present in thedry powder particles in an amount of at least 20 weight percent.
 48. Themethod of claim 46 wherein the drug is present in the dry powderparticles in an amount of at least 40 weight percent.
 49. The method ofclaim 46 wherein the drug is present in the dry powder particles in anamount of at least 50 weight percent.
 50. The method of claim 46 whereinthe particles have a tap density of less than about 0.4 g/cm³.
 51. Themethod of claim 46 wherein the particles have a mass median aerodynamicdiameter of less than about 5 microns.
 52. The method of claim 46wherein the particles have a mass median geometric diameter greater thanabout 5 microns.
 53. The method of claim 46 wherein the particles have amass median aerodynamic diameter of less than about 3 microns.
 54. Themethod of claim 46 wherein the particles include a phospholipid.
 55. Themethod of claim 46 wherein the particles include citrate and amultivalent salt.
 56. The method of claim 46 wherein the particlesinclude an amino acid.
 57. The method of claim 46 wherein the amino acidis leucine.
 58. The method of claim 46 wherein the particles areadministered via a dry powder inhaler.
 59. The method of claim 58wherein the dry powder inhaler is a single dose breath activated drypowder inhaler.
 60. The method of claim 39 further comprisingco-administering at least one additional agent.
 61. A method fortreating a disorder of the central nervous system comprisingadministering to the respiratory tract of a patient in need of treatmenta drug for treating said disorder, wherein the drug is administered in adose that is at least about two times less than that required byadministration routes other than intravenous and wherein delivery is tothe pulmonary system.
 62. A method for treating a disorder of thecentral nervous system comprising administering to the respiratory tractof a patient in need of treatment or rescue therapy ketoprofen, whereinketoprofen is administered in a dose that is at least about two timesless than that required by oral administration and wherein delivery isto the pulmonary system.
 63. A method for treating a disorder of thecentral nervous system comprising administering to the respiratory tractof a patient in need of rescue therapy a benzodiazepine drug, whereinthe benzodiazepine drug is administered in a dose that is at least abouttwo times less than that required by oral administration and whereindelivery is to the pulmonary system.
 64. A method of treating a disorderof the central nervous system comprising: administering to therespiratory tract of a patient in need of rescue therapy particlescomprising an effective amount of a benzodiazepine drug wherein theparticles are delivered to the pulmonary system and the benzodiazepinedrug is released in the blood stream of the patient and reaches its siteof action within a time sufficiently short to provide said rescuetherapy.
 65. The method of claim 64 wherein the rescue therapy is for apanic attack.
 66. The method of claim 64 wherein the benzodiazepine drugis present in the particles in an amount ranging from about 1 to about90 weight percent.
 67. The method of claim 64 wherein the particles havea tap density less than about 0.4 g/cm³.
 68. The method of claim 64wherein the particles have a volume median geometric diameter of betweenabout 5 micrometers and about 30 micrometers.
 69. The method of claim 64wherein the particles have an aerodynamic diameter of between about 1and about 5 microns.
 70. The method of claim 69 wherein the particleshave an aerodynamic diameter of between about 1 and about 3 microns. 71.The method of claim 69 wherein the particles have an aerodynamicdiameter of between about 3 and about 5 microns.
 72. The method of claim64 wherein delivery to the pulmonary system includes delivery to thealveoli.
 73. The method of claim 64 wherein the particles include aphospholipid.
 74. The method of claim 73 wherein the phospholipid has amatrix transition temperature which is no higher than the patient'sphysiological temperature.
 75. The method of claim 73 wherein thephospholipid is present in the particles in an amount ranging from about10 to about 99 weight percent.
 76. The method of claim 64 wherein theparticles include a hydrophobic amino acid.
 77. The method of claim 76wherein the hydrophobic amino acid is present in the particles in anamount of a least 10% by weight.
 78. The method of claim 64 wherein theparticles include citrate.
 79. The method of claim 78 wherein theparticles further include calcium chloride.
 80. The method of claim 64wherein delivery to the pulmonary system is by means of a dry powderinhaler.
 81. The method of claim 64 wherein delivery to the pulmonarysystem is by means of a metered dose inhaler.